Management of breast cancer in women with BRCA gene mutation
Authors: Malcolm R Kell, John P Burke
Journal: BMJ (2007)

Germline mutation may account for up to 10% of breast cancers.1 Known mutations in the BRCA1 and BRCA2 genes are responsible for about 45% of breast cancer susceptibility syndromes (genetic abnormalities that put patients at high risk of developing breast cancer), which are inherited in an autosomal dominant pattern.1 Variants of the BRCA genes increase the overall risk of developing breast cancer and are also associated with a high risk of early onset breast cancer.

Once BRCA1 or BRCA2 mutation has been confirmed, preventative strategies include bilateral prophylactic mastectomy and intensive screening with possible hormonal manipulation. Although prevention of primary breast cancer with mastectomy reduces the risk of breast cancer by 89.5-100%, understandably it is unacceptable to many women.2,3 This is because it has a negative impact on self image, it involves major surgery, it cannot remove all risk, and patients may find it hard to accept its theoretical benefit as not all carriers develop breast cancer.

For women with breast cancer unrelated to BRCA (“sporadic breast cancer”), breast conserving surgery combined with radiotherapy is used where appropriate and is now regarded as the standard of care.4 Conceptually, breast conserving surgery may seem unwise in women with BRCA related breast cancer because of the potential risk of in-breast tumour recurrence. After more than a decade of research the optimal local treatment for these women remains a source of contention.

The largest series to date examined breast conserving surgery in 160 women with BRCA mutation and found a 10 year in-breast tumour recurrence of 12%.5 In women with sporadic breast cancer, the cumulative 10 year in-breast tumour recurrence in five national surgical adjuvant breast and bowel project trials was 8.7%.6 The risk in women with BRCA mutation is therefore slightly higher than in women without, though it seems to be acceptable, as previous trials in women with sporadic breast cancer have reported in-breast tumour recurrence between 10% and 15% at 10 years. Furthermore, when women with BRCA related breast cancer were compared retrospectively with age matched controls with sporadic breast cancer, no significant difference was found in the risk of in-breast tumour recurrence, provided the women with BRCA related breast cancer had undergone bilateral prophylactic oophorectomy.5 However, women with BRCA mutation who did not have prophylactic oophorectomy had twice the rate of in-breast tumour recurrence relative to controls.5

Although the risk of ovarian cancer in women with BRCA mutation is much lower than the risk of breast cancer, bilateral prophylactic oophorectomy reduces the risk of a new breast cancer as a result of hormone deprivation.7 Prophylactic oophorectomy reduces the risk of breast cancer by about 70% in women with BRCA mutation, and short term hormone replacement therapy after surgery does not seem to negate this protective effect.8

Apart from an increased risk of in-breast tumour recurrence, women with BRCA mutation who have breast conserving surgery also have a greater incidence of new primary tumours in the contralateral breast than women with sporadic breast cancer (42% v 9% at 12 years).9 Bilateral prophylactic oophorectomy combined with tamoxifen reduces the risk of contralateral breast cancer by as much as 50% in women with BRCA mutation, supporting hormonal intervention.5 Tamoxifen reduces the risk of in-breast tumour recurrence in these women, and this protective effect increases with the duration of treatment (up to four years).10

The only specific BRCA chemoprevention studies have been small single centre trials. Several randomised controlled trials have assessed tamoxifen as a chemoprevention strategy in high risk patients, however, and post randomisation analysis of those with BRCA mutation has shown tamoxifen to be up to 50% effective in preventing breast cancer in these patients.11 In addition, tamoxifen can reduce the incidence of a second primary cancer by 50% in women with BRCA mutation.11

So what does all this mean for patients and the clinicians advising them? Overall, the evidence indicates that breast conservation is safe in selected women with BRCA related cancers when combined with optimal adjuvant therapy.4 Recent data show that women who have breast conserving surgery rather than mastectomy for breast cancer score higher on quality of life measures, and these findings are probably applicable to women with BRCA mutation.12 However, women with BRCA related breast cancer should be informed of the relative risks and benefits of bilateral prophylactic mastectomy compared with breast conservation so they can be supported in making their own decisions.