Annals of Oncology Advance Access originally published online on June 21, 2005
Annals of Oncology 2005 16(11):1846-1847; doi:10.1093/annonc/mdi351
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© 2005 European Society for Medical Oncology
Letter to the Editor |
Spectrum of breast cancer metastasis in BRCA1 mutation carriers: highly increased incidence of brain metastases
BRCA1 germline mutations lead to breast cancer with specific pathobiological profiles, namely, a high grade, high proliferation rates, and low expression of hormone receptors and Her2. However, such genetically determined tumours have never been associated with specific clinical behaviours, although consistent data suggest that they probably carry a worse prognosis [1
]. We selected from the database of our genetic clinic all BRCA1 or BRCA2 mutation carriers and patients with family history but non-carriers who were treated and followed-up for breast cancer in our institution (1969–2004). We reviewed the prospectively registered case notes of these patients in order to describe the spectrum of metastases observed during the course of the disease in these three categories.
Fifteen of 70 BRCA1 mutation carriers, 12 of 49 BRCA2 mutation carriers and 58 of 254 patients with a family history of breast cancer but no mutation identified, developed metastatic disease. Thirteen of 15 BRCA1 carriers had been screened for mutation because of personal history of breast cancer associated with a family history of breast/ovarian cancer, according to the French Federation of Cancer Centres/INSERM guidelines [2], while two of them had pre-symptomatic BRCA1 testing. In addition, one BRCA2 carrier had pre-symptomatic testing, while 11 were identified as carriers because of personal and family history. All non-carriers had been screened for BRCA1 and BRCA2 mutation because of personal history and pedigree, according to the same guidelines. The median follow-up from the diagnosis of the first metastasis to the last visit or death was, respectively, 17.2 months (range 1.8–42) for BRCA1 patients, 44 months (range 1.8–121) for BRCA2 and 46.5 months (range 1.5–210) for non-carriers. As expected, tumours in BRCA1 carriers expressed estrogen receptors less frequently (Table 1). The spectrum of sites where metastases arose at any time during the course of the disease differed significantly within the three groups. BRCA1 carriers developed less bone (P = 0.01) and more lung (P = 0.005) metastases (Table 1). In addition, 10 of 15 (67%) BRCA1 mutation carriers developed brain metastases, while no (0%) BRCA2 carriers and six of 58 (10.3%) non-carriers did (P = 10–5). In line with the general policy of the centre, none of the patients had undergone screening for brain metastases; all cases were discovered because specific symptoms occurred. In BRCA1 carriers, the median time from the diagnosis of the first metastasis to that of brain involvement was 7.8 months (range 0–25). At follow-up, 12 of 15 BRCA1 carriers (80%), nine of 12 BRCA2 (75%) and 40 of 58 non-carriers (69%) had died. The shorter median follow-up registered among BRCA1 carriers seemed to be mostly related to shorter survival after the diagnosis of metastatic breast cancer, although the limited size of the sample prevents from any conclusion regarding this observation.
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Cerebral metastases have recently become a significant clinical problem for physicians entrusted with the care of breast cancer patients, because they occur more frequently and treatment is difficult [3
]. This is particularly true for patients whose tumours overexpress Her2, in which case the incidence of brain metastases rises to 30–40% [4]. In a previous study, we identified lung metastases and negative hormone receptors as major independent risk factors for brain metastases [5]. In the present series, patients with germline BRCA1 mutations had the highest incidence of brain metastases from breast cancer ever described. This finding, in the context of a very specific genetic background, is another piece of the complex puzzle of biological determinants of cancer behaviour and metastatic pathways. Our data may also have implications for management in this particular patient population: systematic screening for brain metastases may be considered when metastatic disease occurs, as well as proposals for prevention strategies, such as those developed for lymphoma or non-small-cell lung cancer patients [6].
Departments of 1 Medicine and 2 Radiology, Institut Gustave Roussy, Villejuif, France
* E-mail: delaloge{at}igr.fr
References
1. Robson ME, Chappuis PO, Satagopan J et al. A combined analysis of outcome following breast cancer: differences in survival based on BRCA1/BRCA2 mutation and administration of adjuvant treatment. Breast Cancer Res 2004; 6: R8–R17.[CrossRef][Web of Science][Medline]
2. Eisinger F, Alby N, Bremond A et al. Recommendations for medical management of hereditary breast and ovarian cancer: the French National Ad Hoc Committee. Ann Oncol 1998; 9: 939–950.
3. Crivellari D, Pagani O, Veronesi A et al. International Breast Cancer Study Group. High incidence of central nervous system involvement in patients with metastatic or locally advanced breast cancer treated with epirubicin and docetaxel. Ann Oncol 2001; 12: 353–356.
4. Slimane K, André F, Delaloge S et al. Risk factors for brain relapse in patients with metastatic breast cancer. Ann Oncol 2004; 11: 1640–1644.
5. Lai R, Dang CT, Malkin MG, Abrey LE. The risk of central system metastases after trastuzumab therapy in patients with breast carcinoma. Cancer 2004; 101: 810–816.[CrossRef][Web of Science][Medline]
6. Auperin A, Arriagada R, Pignon JP et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic cranial irradiation overview collaborative group. N Engl J Med 1999; 341: 476–484.
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