When is urgent DNA testing needed?
Tumour treatment must be the priority in diagnosing breast cancer.
Urgent DNA testing for a mutation in the BRCA1/2 gene can be considered if it might influence the woman’s choice for local treatment of the primary cancers with consequences for survival.
Women who might be eligible for this are:
- those with a high risk of a BRCA1 or 2 mutation
- young women (under age 40) with very early stage breast cancer
Since advice on whether to initiate urgent DNA testing for BRCA1/2 mutations is highly complex, at a minimum the decision should be shared by the clinical geneticist, the medical oncologist and the surgical oncologist, and referral to a centre with expertise is advisable.
The women must be told that prophylactic contralateral mastectomy (PCM) will barely affect survival, but will strongly reduce their risk of contralateral breast cancer.
There is no clear contraindication for breast-conserving therapy in the presence of an identified BRCA1/2 gene mutation.
Level 2: B Liebens 2007, Brekelmans 2007, Garcia-Etienne 2009
There is a markedly increased risk of contralateral breast cancer in BRCA1/2 gene mutation carriers. Risk-reducing mastectomy significantly reduces the risk of a second diagnosis of breast cancer.
Level 2: B Liebens 2007, Domchek 2010
Risk-reducing contralateral mastectomy has been found to have no clear survival benefit. The survival is primarily determined by the prognosis and therapy of the primary breast carcinoma.
Level 2: B Brekelmans 2007, van Sprundel 2005
After risk-reducing salpingo-oophorectomy in BRCA1/2 mutation carriers, there is a significantly lower risk of breast cancer, a decrease in mortality from all causes but also from breast cancer- and ovarian cancer-induced mortality.
Level 3: B Domchek 2010
Urgent diagnostic testing for a DNA defect causing breast cancer could be meaningful when there is concern that the presence of a hereditary diseasemight influence the choice for local treatment with consequences for survival. A woman with breast cancer due to a BRCA1 or 2 mutation is not only has a risk of recurrence, but also at increased risk of a second primary tumour, usually contralateral. This risk is also affected by other factors: her age at the time the primary breast cancer was diagnosed, adjuvant therapy of the primary breast cancer (radiation therapy, chemotherapy and/or hormone therapy) and prophylactic adenectomy.
When urgent DNA testing is indicated, it is important to know:
a. If a mutation is diagnosed, is a particular primary treatment preferred, in view of the chance of recurrence?
b. Could a simultaneous prophylactic contralateral mastectomy (PCM) have a clear survival benefit?
Regarding a: Risk of ipsilateral recurrence
In a systematic review, BRCA mutation carriers in 5 of the 17 studies had an elevated risk of an ipsilateral recurrence, and in 4 of the 14 studies poorer survival rates [Liebens, 2007]. In a study published later, 223 breast cancer patients with a BRCA1 mutation, 103 breast cancer patients with a BRCA2 mutation, 311 breast cancer patients with a high familial risk but without gene mutation, and 759 breast cancer patients with no family history, the risk of an ipsilateral recurrence did not differ between these 4 groups. The incidence after 10 years in each of these groups was 16%, 17%, 15% and 21%, respectively [Brekelmans, 2007]. In a comparison of 54 breast cancer patients with a BRCA1/2 mutation who were matched with 162 patients with sporadic breast cancer, Garcia-Etienne (2009) reports a 10-year cumulative incidence of ipsilateral recurrence of 27% for the mutation carriers and 4% for the sporadic controls.
The studies done by Pierce (2010) and Kirova (2010) also report a slightly greater chance of ipsilateral recurrence, but it did not affect survival. Metcalfe (2011) followed 396 mutation carriers who had BCT; the risk of ipsilateral recurrence was 1.2% per year. The risk was lower in women who were treated with radiation therapy, chemotherapy or oophorectomy. Currently there are no strong arguments for treating diagnosed breast cancer in BRCA mutation carriers differently from non-mutation carriers.
Regarding b: Risk of contralateral breast cancer
Various large studies have shown that there is a markedly increased risk of a second diagnosis of breast cancer in BRCA gene mutation carriers. Liebens found this in 14 of the 16 studies [Liebens, 2006]. The 10-year risk of contralateral breast cancer varied from 25-31% for BRCA mutation carriers compared to 4-8% for sporadic breast cancer. More recent studies confirmed the strongly increased risk of a contralateral tumour. Graeser (2009) found that over 47% of the BRCA breast cancer patients had developed a contralateral tumour after 25 years. A younger age at the time of the first tumour meant a significantly higher risk: 63% of the patients with a BRCA1 mutation who were under age 40 at the time of the first breast cancer had developed contralateral breast cancer 25 years later, compared to 20% of those over age 50 at the time of the first breast cancer . The studies of van der Kolk (2010) and Malone (2010) are also consistent with these results.
The study of Domchek (2010), a multicentre cohort of 2,482 women with a BRCA1/2 mutation, describes the effects of risk-reducing surgery. Risk-reducing mastectomy was associated with a significantly lower risk of breast cancer. No breast cancers were found in a group of 247 women who had undergone risk-reducing mastectomy. There was no clear survival benefit after risk-reducing mastectomy. After correcting for stage and therapy, Brekelmans (2007) found that a contralateral carcinoma did not affect survival. Van Sprundel (2005) showed survival benefit from PCM in 145 BRCA1/2 mutation carriers in univariate analysis, but not in multivariate analysis. In this study it was found that survival was determined by the characteristics of the primary carcinoma. In a small study, Peralta (2000) did find better disease-free survival after PCM, but no difference in survival. Heron (2000) showed, studying 1,465 patients, that survival was no worse after contralateral breast cancer.
In Domchek's (2010) study, risk-reducing (preventive) bilateral salpingo-oophorectomy (pBSO) was associated with a significantly lower risk of ovarian cancer in both BRCA1 and BRCA 2 mutation carriers and in those with and without a history of breast cancer. After pBSO in both BRCA1 and BRCA2 mutation carriers, there is a significantly lower risk of breast cancer, a decrease in mortality from all causes but also from breast cancer- and ovarian cancer-induced mortality.
Authorization date and validity
Last review : 13-02-2012
Last authorization : 13-02-2012
Initiative and authorization
Initiative : Nationaal Borstkanker Overleg NederlandAuthorized by:
- Nederlandse Internisten Vereniging
- Nederlandse Vereniging voor Heelkunde
- Nederlandse Vereniging voor Pathologie
- Nederlandse Vereniging voor Radiologie
- Nederlandse Vereniging voor Radiotherapie en Oncologie
Method of development
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