1 MSC Cancer Centre, Gliwice; 2 MSC Cancer Centre, Warsaw; 3 Wielkopolska Cancer Centre, Pozna, Poland
* Correspondence to: Dr J. Rogoziska-Szczepka, MSC Cancer Centre, Gliwice, Poland. Tel: +48-32-2788717; Fax: +48-32-2788716; Email: utracka{at}io.gliwice.pl
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Abstract |
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Patients and methods: A group of 108 patients with bilateral breast cancer, who reported at our Cancer Centres from 2000 to 2002, were subjected to genetic testing. Similarities and differences between BRCA1/2 carriers and non-carriers were analysed in terms of family history, pathology of tumour, age of diagnosis, developing contralateral BC and second primary cancer.
Results: BRCA1/2 mutations were detected in 32 of 108 patients. Family history of BC was identified in 46.9% of these patients compared with 22.4% of non-carriers (P <0.05). Synchronous BC was diagnosed significantly rarer [4 of 32 (12.5%)] in BRCA1/2 carriers than in the non-carrier group [26 of 76 (34.2%)]. In addition, patients with BRCA mutations were younger when they were diagnosed than non-carriers. BRCA1/2 carriers had a significantly higher incidence of medullary BC (13.6% versus 1.7%) and developed ovarian cancer significantly more frequently than non-carriers (12 of 32 and 1 of 72 patients, respectively).
Conclusions: Patients with bilateral BC having BRCA mutations are significantly younger than non-carriers. They also have a significantly higher family history of BC and an increased risk of developing ovarian cancer. The differences in clinical aspects of BRCA carriers with bilateral BC should be considered in clinical management.
Key words: bilateral breast cancer, BRCA1/2, prognostic factors
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Introduction |
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About 10% of breast cancer patients carry germ-line mutations that predispose them to inherited disease [5]. The lifetime risk of developing breast cancer is 4687% for BRCA1 and 2684% for BRCA2 carriers by the age of 70 [6
, 7
, 8
, 9
] in contrast to a 10% risk in the overall population [10
].
BRCA carriers also run a greater risk of developing breast cancer before menopause and a significantly higher risk of developing contralateral breast cancer in contrast to the general population: 53% versus 2% respectively, according to Nicolletto et al. [5].
The objective of our study was to evaluate the risk of developing contralateral breast cancer and a general description of patients with bilateral breast cancer. The results presented here will help to identify women with a high risk of developing a second primary malignancy and should be considered in the clinical management of these patients.
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Patients and methods |
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Patients with synchronous breast cancer were defined as having contralateral breast cancer within 1 year after excluding local spread of primary breast cancer towards contralateral breast. Metachronous breast cancer was defined as contralateral breast cancer diagnosed more than 1 year after primary diagnosis of breast cancer and after exclusion of distant metastases and locoregional recurrence of primary breast cancer. After giving their written informed consent, 10 ml of blood was drawn from 108 patients for genetic testing. DNA was isolated from leukocytes according to the phenolchloroform extraction method. The carriers of germline mutations were asked to give a second blood sample to confirm the positive result. When the test results were available, patients were offered full genetic counseling. The consent process was approved by the local ethics committee.
Allele specific amplification (ASA) and restriction fragment length polymorphism (RFLP) PCRs were carried out as described by Chan et al. [11] and Grzybowska et al. [12
].
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Results |
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Mean age of patients with synchronous and metachronous breast cancer was 52 (range 3376) and 45 years (range 2876), respectively. Positive family history in first- and second-degree relatives was reported in 35 patients (30 with breast cancer, three with ovarian cancer and two with ovarian and breast cancer).
Of 108 patients, 32 (29.6%) carried germline mutation, 31 in the BRCA1 gene and one in the BRCA2 gene. In BRCA1 carriers, family history of breast cancer was reported in 46.9% of patients in contrast to 22.4% of non-carriers (P <0.05) and ovarian cancer in 12.5% and 1.3% of patients, respectively (P <0.05). Synchronous bilateral breast cancer was significantly rarer [4 of 32 (12.5%)] among BRCA carriers in contrast to non carriers [26 of 76 (34.2%)] (Table 1).
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BRCA carriers with bilateral breast cancer had a significantly higher risk of developing ovarian cancer than non-carriers, 12 of 32 (37.5%) versus 1 of 76 patients (1.3%), respectively (Table 2). Ovarian cancer was diagnosed in metachronous bilateral breast cancer patients only mainly as the third primary cancer. Only in two patients was ovarian cancer synchronous with contralateral breast cancer and in one patient it was diagnosed 4 years before contralateral breast cancer (Table 3). Ovarian cancer was the only malignancy diagnosed in BRCA1 carriers with bilateral breast cancer. In the non-carriers group, other non-breast primary malignancies were diagnosed in 10.5% (8/76) of patients: four endometrial cancers and one each of ovarian, lung, colon and gastric cancer.
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Discussion |
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Family history of breast cancer is the other factor which strongly increases the risk of bilateral breast cancer [2, 15
, 16
]. On the other hand, other studies [17
, 18
] failed to find a significant relationship between familial breast cancer and contralateral breast cancer. Our findings correspond with those authors who found that incidence of bilateral breast cancer is greater in women with a family history. Familial breast cancer in our study was recognised in 30% of patients with bilateral breast cancer.
According to some authors, it is established that women with lobular histology develop second primary breast cancer more frequently [16, 19
, 20
], whereas others did not find the correlation between lobular histology and risk of contralateral breast cancer [21
, 22
]. In our study, no correlation between histology and risk of bilateral breast cancer was found. Although in the BRCA1 carrier group, a significantly higher incidence of medullary breast cancer was diagnosed (13.6% versus 1.7%). Medullary carcinoma with lymphocyte infiltration is normally rare (2%) but according to some authors, it is more frequently associated with BRCA1 alteration [23
26
].
In BRCA carriers, there is a lifetime risk of developing breast cancer of 5087% by the age of 70 years, and the risk of developing contralateral breast cancer is 3264% [5, 8
, 27
, 28
]. One study found four to five times more contralateral breast cancer in BRCA1 mutation carriers as compared with sporadic breast cancer [29
]. This corresponds with our data, where in our highly selected group of 108 patients with bilateral breast cancer, there is a high frequency of BRCA carriers (29.6%) similar frequencies of 29.6% [30
] and 22% [31
] have been reported elsewhere. Turner et al. [32
] reported a 15% frequency of BRCA1/2 mutation in a group of patients with ipsilateral breast tumour recurrence. This is not exactly the same group as ours. But five of eight patients with BRCA1/2 mutations in this study had bilateral breast cancer, confirming other reports of a high risk of contralateral breast cancer [32
].
In contrast to these data, Steinmann et al. [33] did not find higher frequencies of BRCA mutation in a group of 75 patients with bilateral breast cancer. In this study, the frequencies of BRCA mutations between bilateral and unilateral breast cancer were not different.
In our study, patients with BRCA1 mutations when diagnosed were younger than non-carriers (42 versus 49.5 years). Family history of breast cancer identified in BRCA carriers was significantly higher [15 of 32 (46.9%)] than in non-carriers [17 of 76 (22.4%)]. Also it is important to note that in our study BRCA1 carriers developed ovarian cancer significantly more frequently than non-carriers [12 of 32 (37.5%) versus 1 of 76 (1.3%)]. Although in non-carriers with bilateral breast cancer, there was a higher incidence of other primary cancers (seven of 76 patients) other than ovarian cancer. In our study, high ovarian cancer risk (37.5%) is most probably due to the selected group of patients with bilateral breast cancer, so the frequency of mutations is obviously higher than in consecutive cases of breast or ovarian cancer in population-based studies [9]. This is the first study of bilateral breast cancer in Poland.
According to Dawson et al. [34], hereditary breast cancer is characterised by an age of onset <45 years of age, bilaterality, an autosomal dominant pattern of inheritance and a greater frequency of other primary cancers.
Our study confirms that BRCA1 carriers with breast cancer have a high lifetime risk of contralateral breast cancer and ovarian cancer. According to Ford et al. [8], their risk of developing either breast cancer or ovarian cancer is close to 100% and carriers previously with one cancer have a high risk of developing contralateral breast cancer or ovarian cancer and need to be managed accordingly.
The general approach for contralateral breast cancer prevention includes dietary modification, prophylactic surgery, surveillance, chemoprevention and ovarian ablation. A detailed discussion on these approaches is beyond the scope of this paper. Nevertheless, we agree with some authors [3, 5
, 8
, 28
, 34
] that BRCA1 carriers need more aggressive monitoring. When diagnosed with breast cancer before the age of 50 years, prophylactic mastectomy and/or prophylactic oophorectomy should be considered.
In summary, this study found that BRCA1 carriers with bilateral breast cancer are diagnosed at younger age, have an increased rate of family history and a higher risk of developing ovarian cancer than non-carriers. These findings point to an hereditary factor. The differences in the clinical aspects of BRCA carriers with bilateral breast cancer should be considered in their clinical management.
Received for publication February 11, 2004. Revision received May 4, 2004. Accepted for publication May 6, 2004.
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