Risk-reducing Strategies for Women Carrying brca1/2 Mutations with a Focus on Prophylactic Surgery

Mohamed Salhab; Selina Bismohun; Kefah Mokbel


BMC Womens Health. 2010;10(1) 

In This Article


Breast cancer remains the leading cause of death in women aged 40–55 years.[1] Sporadic breast cancer accounts for 70–80% of all cases.[2] It is estimated that 5–10% of all breast cancers and 25%-40% of breast cancers affecting women younger than 35 years of age are attributable to hereditary causes.[2] Furthermore 60%-70% of hereditary breast cancers seem to arise secondary to germline mutations in the BRCA1 and BRCA2 genes.[3,4] Notably, ovarian cancer is a relatively rare disease: it affects one in eighty women at some point during their life time.[5] Hereditary or familial ovarian cancer is linked to many germline mutations, such as PTEN (Cowden syndrome), TP53 (Li-Fraumeni Syndrome) and ATM (ataxia-teleangiectatica-mutated gene).[6] However, BRCA1 and BRCA2 gene mutations are found to cause the majority of autosomal-dominant inherited ovarian cancer.[6]

Histologically, BRCA1-related breast cancers are predominantly of the basal subtype, with predominant lymphocytic infiltration, and are often more aggressive and associated with negative prognostic factors, as characterised by numerous mitoses, pleomorphic pattern, poor differentiation and higher proliferation rates,[7–11] as well as a negative oestrogen and progesterone receptors status.[8,10,12] Moreover, a lack of HER-2 expression was observed in breast cancer tumours of BRCA1 carriers.[13] On the other hand, tumours associated with BRCA2 mutations are of a luminal subtype, and tend to be of a positive oestrogen and progesterone receptors-status; negative HER-2, on the other hand, do not markedly differ from other hereditary or sporadic breast cancers.[14] DCIS is found to be equally as prevalent in patients who carry deleterious BRCA mutations as in high familial-risk women who are non-carriers, but ultimately occurs at an earlier age. Interestingly, BRCA mutations were found in a significant portion of women with DCIS who were presented for a hereditary risk assessment.[15] Notably, high-grade DCIS is also more common in BRCA1 mutation carriers than in those patients without any mutation.[16] Accordingly, it has been suggested that BRCA1/2-associated breast cancers progress through the same intermediate steps as sporadic breast cancers, and that DCIS should be considered as a part of the BRCA1/2 tumour spectrum.[17]

Clinically, breast cancer is believed to begin at an earlier age in BRCA1 and BRCA2 gene mutation carriers compared with sporadic cases. The median age of breast cancer onset ranges from 40–50 years in BRCA1 and BRCA2 carriers compared with 60–70 years in sporadic cases.[18,19] Furthermore, breast tumours in BRCA1/2 carriers are more likely to be bilateral and affect the contra lateral breast at a later stage.[8,12,19] Furthermore, BRCA1/2 mutation carriers also have a higher rate of pregnancy-associated breast cancer before the age of 50.[20,21]

Several studies have suggested no significant differences between BRCA-associated breast cancer and non-BRCA associated breast cancer in relapse-free, event-free, and overall survival.[22–24] On the other hand, other studies indicate that BRCA-associated breast cancer presents worse survival rates and overall prognosis.[14,25–28] Inconsistencies in previous studies may be due to limitations in study design: in particular, the studies contain small numbers of BRCA cases. Additionally, due to the onset occurring at an extremely early age of those patients with BRCA mutations, it was not always possible to obtain controls which were considered adequately matched for age. In addition, inconsistencies in previous studies were due to the examination of both BRCA1 and BRCA2 mutation groups together. Lee et al., for example, recently conducted a meta-analysis of 11 previously published articles.[29] The analysis shows that the BRCA1 mutation carriers have worse predicted overall survival rates (approximately 5 years) than non-carriers (HR = 1.94, 95% CI, 1.45–2.53). Furthermore, long-term overall survival (10 years or greater) was found to be worse in BRCA1 mutation carriers compared with non-carriers (HR = 1.33, 95% CI, 1.12–1.58). However, they indicate that there has been no significant heterogeneity observed across the studies.

Moreover, Lee et al. observes that short-term progression-free survival in BRCA1 carriers was worse than in non-BRCA carriers (HR = 1.54). Such observations were not witnessed in long-term progression survival. In addition, BRCA2 mutation was not observed to affect either short- or long-term survival rates, which may be attributed to the different carcinogenic pathways for BRCA1 and BRCA2.[29]

Most ovarian cancers associated with germ line BRCA mutations are diagnosed at a younger age and are ultimately determined as high-grade and advanced-stage serous carcinomas.[30] They have surgical and pathological characteristics similar to those of sporadic cancers. BRCA mutations do not seem to play a significant role in the development of mucinous or borderline ovarian tumours.[21] Moreover, BRCA1 germline mutation carriers are not only at risk of ovarian cancer, but also fallopian tube carcinoma and peritoneal papillary serous carcinoma.[31] Olivier et al. suggest that peritoneal papillary serous carcinoma risk amongst BRCA2 carriers is lower than amongst BRCA1 carriers.[31] Furthermore, hereditary ovarian cancer has a distinctly better clinical outcome with a longer overall survival and recurrence-free interval after chemotherapy than sporadic cancers.[21] Notably, it has been observed that BRCA-positive Epithelial Ovarian Cancer patients have better outcomes than non-hereditary epithelial ovarian cancer patients,[32] and advanced-stage hereditary cancer patients survive longer than nonhereditary cancer patients.[33]

The identification of BRCA1 and BRCA2 genes in 1994 and 1995 respectively[34,35] has had a great impact on the understanding and management of sporadic and hereditary breast and ovarian cancers. Whilst the risk of breast and ovarian cancer in the general population is 10%-13% and 1.7%, respectively, studies indicate that a woman with mutations in either BRCA1 or BRCA2 carries a lifetime breast cancer risk of 80% and 20%-60% for developing breast cancer and ovarian cancer respectively.[3,36] In the case of BRCA1 gene mutation carriers, the cumulative risk of cancer by the age of 70 years ranges between 51% and 95% for breast cancer, and between 22% and 60% for ovarian cancer. Similar trends are also observed in BRCA2 carriers, as the risk ranges between 33% and 95% for breast cancer, and between 4% and 47% for ovarian cancer.[37]

Women who have an increased risk of breast and ovarian cancer are advised to consider risk-reducing strategies; however, such methods vary in their effectiveness. These strategies include surveillance (breast self-examination, clinical breast examination, screening using mammography and breast magnetic resonance imaging (MRI), trans-vaginal ultrasound scanning and serum (CA125), chemoprevention and prophylactic surgery (salpingo-oophorectomy and/or mastectomy).[38,39] Risk-reducing strategies have been shown to have associations with a gain in life expectancy in BRCA1/2 carriers. Moreover, extended life expectancy can range from between a few months to a few years, although this is ultimately dependent on the prophylactic intervention (Table 1).

The aim of this review is to provide an up-to-date analysis and to subsequently summarise the available literature in relation to risk-reducing strategies, with a keen focus on prophylactic surgery.


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