Original article

Annals of Oncology 15: 1373 1376, 2004 doi:10.1093/annonc/mdh352

BRCA1 and BRCA2 mutations as prognostic factors in bilateral breast cancer patients
J. Rogozinska-Szczepka1*, B. Utracka-Hutka1, E. Grzybowska1, B. Ma 1, E. Nowicka1, ka 1 1 2 cka A. Smok-Ragankiewicz , H. Zientek , J. Steffen & A. Wojciechowska-a 3
1

MSC Cancer Centre, Gliwice; 2MSC Cancer Centre, Warsaw; 3Wielkopolska Cancer Centre, Poznan, Poland

Received 11 February 2004; revised 4 May 2004; accepted 6 May 2004

Background: Incidence of primary bilateral breast cancer (BC) is rare and does not exceed 5%. BRCA1/2 mutation carriers diagnosed with breast cancer have a strong life time risk of developing contralateral breast cancer (53% versus 2%). 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 identied in 46.9% of these patients compared with 22.4% of non-carriers (P <0.05). Synchronous BC was diagnosed signicantly 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 signicantly higher incidence of medullary BC (13.6% versus 1.7%) and developed ovarian cancer signicantly more frequently than non-carriers (12 of 32 and 1 of 72 patients, respectively). Conclusions: Patients with bilateral BC having BRCA mutations are signicantly younger than noncarriers. They also have a signicantly 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
Bilateral breast cancer is rare and its incidence varies according to different authors from 1 to 14% [13], and several studies have demonstrated an annual risk of contralateral breast cancer of 0.5 0.8%. A high risk group of patients with bilateral breast cancer has been identied who present with either early onset of the disease and/or a family history of breast cancer. Those diagnosed with synchronous breast cancer have a decreased overall survival and local control compared with women who have either metachronous or unilateral disease [4]. 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 signicantly 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.

Patients and methods

A group of 108 consecutive patients with bilateral breast cancer reporting to MSC Cancer Centre, Gliwice (94 patients) and Wielkopolska Cancer Centre (14 patients) from 2000 to 2002, and who gave their written informed consent for genetic testing, were the subject of our analysis. Information regarding family history, mainly concerning breast and ovarian cancer incidence in both rst- and second-degree relatives, was obtained from each patient.

*Correspondence to: Dr J. Rogozinska-Szczepka, MSC Cancer Centre, Gliwice, Poland. Tel: +48-32-2788717; Fax: +48-32-2788716; E-mail: utracka@io.gliwice.pl
q 2004 European Society for Medical Oncology

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Patients with synchronous breast cancer were dened as having contralateral breast cancer within 1 year after excluding local spread of primary breast cancer towards contralateral breast. Metachronous breast cancer was dened 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 phenol chloroform extraction method. The carriers of germline mutations were asked to give a second blood sample to conrm 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 specic amplication (ASA) and restriction fragment length polymorphism (RFLP) PCRs were carried out as described by Chan et al. [11] and Grzybowska et al. [12]. Table 1. Characteristics of BRCA carriers and non-carriers with bilateral breast cancer BRCA carriers (n = 32) Age at rst diagnosis of BC, years Mean (range) Positive family history of BC Positive family history of OC Synchronous disease 42.06 (2962) 15/32 (46.9%) 4/32 (12.5%) 4/32 (12.5%) 49.43 (2876) 17/76 (22.4%) 1/76 (1.3%) 26/76 (34.2%) 0.0109 0.0128 0.0235 BRCA non-carriers (n = 76) P value

Age at diagnosis of synchronous BC Mean (range) Metachronous disease 47.25 (3662) 28/32 (87.5%) 52.4 (3376) 50/76 (65.8%)

Age at diagnosis of metachronous BC

Results
A group of 108 patients with bilateral breast cancer was studied. Of these, 30 (28%) had synchronous and 78 (72%) metachronous breast cancer with a median time of 7 years (range 129) between diagnosis of primary and contralateral breast cancer. Mean age for all 108 patients with bilateral breast cancer when rst diagnosed was 47 years (range 28 76). The majority of patients (73%) were under 50 years and 22% were under 40 years of age. Mean age of patients with synchronous and metachronous breast cancer was 52 (range 33 76) and 45 years (range 28 76), respectively. Positive family history in rst- 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 signicantly rarer [4 of 32 (12.5%)] among BRCA carriers in contrast to non carriers [26 of 76 (34.2%)] (Table 1). Metachronous breast cancer BRCA carriers when rst diagnosed were signicantly younger (42 years) than non-carriers (49.5 years). Eighty-nine per cent of metachronous tumours found in mutation carriers presented within the rst 10 years of follow up, in contrast to 78% of non-carriers; the difference was not signicant. Mean interval time between the rst and second breast cancer diagnosis was similar in both groups (6.6 and 7.2 years, respectively). BRCA carriers with bilateral breast cancer had a signicantly higher risk of developing ovarian cancer than noncarriers, 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

Mean (range)

41.3 (2954)

47.9 (2876)

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BC, breast cancer; OC, ovarian cancer.

Table 2. Incidence of third primary malignancies in BRCA carriers and non-carriers with bilateral breast cancer Cancer type Ovarian Stomach Uterine Lung Colorectal BRCA carriers (n = 32) 12/32 0 0 0 0 BRCA non-carriers (n = 76) 1/76 1/76 4/76 1/76 1/76

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. One hundred and eight patients developed 216 tumours of the breasts. Histopathological type of tumour was reported in 158 of tumours (73%). BRCA carriers had a signicantly higher incidence of medullary breast cancer than non-carriers (13.6% and 1.7% respectively). The distribution of other histopathology patterns was similar in both groups of non-carriers and carriers (Table 4).

Discussion
Young age at primary breast cancer diagnosis is associated with an increased susceptibility to bilateral breast cancer, mainly due to the likelihood of living long enough to develop contralateral breast cancer. Bilateral breast cancer is more frequent among women under 50 years of age at rst diagnosis [2]. As reported by Adami et al. [2, 13] and Gogas et al. [14], the mean age of diagnosis for unilateral breast cancer was 63.5 and 54.8 years of age, respectively. Some authors [4] did not nd a statistically signicant difference between

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Table 3. Bilateral breast cancer and ovarian cancer in BRCA carriers (n = 12) Age at diagnosis, years BC (BC1) 37 44 41 31 33 48 46 40 35 29 40 BC, breast cancer. Contralateral BC (BC2) 47 48 46 33 35 52 47 43 45 51 42 Ovarian cancer (OVC) 51 53 54 41 48 48 47 48 49 53 42 Time interval, years BC1 to BC2 10 4 5 2 2 4 1 3 10 22 2 BC1 to OVC 14 9 13 10 15 0 1 8 14 24 2

Table 4. Histopathological features of BRCA carriers and non-carriers with bilateral breast cancer Histopathology Ductal carcinoma Lobular carcinoma Medullar carcinoma Tubular carcinoma DCIS Mixed tubular and lobular carcinoma BRCA carriers (n = 44) 33 (75%) 3 (6.8%) 6 (13.6%) 0 1 (2.2%) 0 BRCA non-carriers (n = 114) 84 (74%) 15 (13.1%) 2 (1.7%) 6 (5.3%) 5 (4.3%) 2 (1.7%) 0.94 0.31 0.0025 0.13 0.54 0.38 P value

the median age of unilateral, metachronous and synchronous breast cancer patients. Our data is in agreement with the previous studies in respect of the patients age. Our group of patients with bilateral breast cancer were younger than 50 years of age when rst diagnosed. The median age for the entire group with bilateral breast cancer was 47 years of age. 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 nd a signicant relationship between familial breast cancer and contralateral breast cancer. Our ndings 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 nd 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 signicantly higher incidence of medullary breast cancer was diagnosed (13.6% versus 1.7%). Medullary carcinoma with lymphocyte inltration is normally rare (2%) but according to some authors, it is more frequently associated with BRCA1 alteration [2326]. 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 32 64% [5, 8, 27, 28]. One study found four to ve 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 ve of eight patients with BRCA1/2 mutations in this study had bilateral breast cancer, conrming other reports of a high risk of contralateral breast cancer [32]. In contrast to these data, Steinmann et al. [33] did not nd 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 identied in BRCA carriers was signicantly higher [15 of 32 (46.9%)] than in noncarriers [17 of 76 (22.4%)]. Also it is important to note that in our study BRCA1 carriers developed ovarian cancer signicantly 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 populationbased studies [9]. This is the rst 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 conrms 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 modication, prophylactic surgery, surveillance, chemoprevention and ovarian ablation. A detailed discussion on these approaches is beyond the scope of

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1376 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 ndings 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.
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