Hereditary breast and ovarian cancer
© The Author(s) 2008
Published: 15 June 2008
Familial breast cancer was first recognized in the Roman medical literature of 100 AD . The first documentation of familial clustering of breast cancer in modern times was published by Broca, who reported 10 cases of breast cancer in 4 generations of his wife's family . In the middle of the nineteen nineties it was proven at the molecular level that a substantial number of breast and ovarian cancers has hereditary monogenic aetiology [3, 4]. Evaluation of frequency of pedigree-clinical signs characteristic for strong aggregations of breast/ovarian cancers among consecutive cases of cancers of these organs as well as analyses of cancer incidence in monozygotic twins indicate that about 30% of breast and ovarian cancers develop because of a strong genetic predisposition . In other breast/ovarian cancers the significance of genetic factors was underestimated. However, recently it has been possible to show the characteristic constitutional background influencing development of cancer also in patients with sporadic neoplasms. Therefore now scientists think that in almost all patients with cancer a certain genetic background should be detectable, although influencing cancer risk to a various degree. Genetic abnormalities strongly related to cancer are called high risk changes (genes) and abnormalities influencing cancer development to a lower degree are called moderate risk changes (genes). Most frequently strong genetic predisposition to breast/ovarian cancers are related to mutations in the BRCA1 and BRCA2 genes and most often it appears as syndromes of hereditary breast cancer -site-specific (HBC-ss), hereditary breast-ovarian cancer (HBOC) and hereditary ovarian cancer (HOC).
Pedigree-clinical diagnostic criteria of HBC-ss, HBOC and HOC syndromes 
Number of breast or ovarian cancer cases in family:
A - 3 (definitive diagnosis)
1) At least 3 relatives affected with breast or ovarian cancer diagnosed at any age
B - 2 (highly probable diagnosis)
1) 2 breast or ovarian cancer cases among first degree relatives (or second degree through male line)
2) 1 breast cancer and 1 ovarian cancer diagnosed at any age among first degree relatives (or second degree through male line)
C - 1 (highly probable diagnosis)
1) Breast cancer diagnosed below 40 years of age
2) Bilateral breast cancer
3) Medullary or atypical medullary breast cancer
4) Breast and ovarian cancer in the same person
5) Breast cancer in male
Risk of breast and ovarian cancer in BRCA1 mutation carriers in Poland 
A. Cumulated risk of breast cancer
Cumulated risk (%)
B. Cumulated risk of ovarian cancer
Cumulated risk (%)
Incomplete penetrance of BRCA1 suggests that other factors, genetic and non-genetic modifiers, are important in carcinogenesis in the mutation carriers. The risk of ovarian cancer is modified by VNTR locus for HRAS 1 and is increased 2-fold in BRCA1 carriers harbouring one or two rare alleles of HRAS 1 . We reported that the 135G>C variant in the RAD51 gene is strongly protective (OR = 0.5) against both ovarian and breast cancer [12, 13].
Carriers of a BRCA1 mutation are also at about 10% lifetime risk of fallopian tube and peritoneal cancers . These data about the frequency of ovarian cancer in BRCA1 carriers appear to reflect the combined frequency of ovarian, fallopian tube and peritoneal cancers, because these tumours were diagnosed as ovarian cancers in the past, and because they share similar morphology and cause elevated levels of the marker CA 125.
The risk of cancer at other sites may be increased in carriers of a BRCA1 mutation as well, but the evidence is controversial and needs further studies.
Molecular diagnosis of constitutional BRCA1 mutations
This topic has been described in detail in the section "BRCA1 Test".
Patients with this syndrome have a constitutional mutation in the BRCA2 gene . According to literature data lifetime risk for BRCA2 carriers from families with definitive HBC-ss and HBOC is estimated at 31-56% for breast cancer and 11-27% for ovarian cancer [10, 25–28]. Studies performed in 200 Polish families with strong aggregation of breast and/or ovarian cancers proved that mutations in the BRCA2 gene are rare, with a frequency of 4%. There are no studies on cumulated cancer risk in BRCA2 mutation carriers from the Polish population. Most BRCA2 mutations from the Polish population probably slightly increase breast cancer risk. Studies performed in our centre showed that in families with aggregation of breast cancer diagnosed before the age of 50 and stomach cancer diagnosed in males before the age of 55, frequency of BRCA2 carriers is about 10-20% . BRCA2 mutations are also related to a significantly increased although not precisely estimated risk of ovarian cancer and cancers of the digestive tract such as stomach, colon and pancreas in both females and males. Studies performed in our centre showed that BRCA2 mutations are detected with a frequency of 30% in families without breast cancer but with aggregation of ovarian cancer with stomach, colon or pancreatic cancer between first and second degree relatives . BRCA2 studies performed on male breast cancer patients from the Poznań population showed that 15% of patients from this group are mutation carriers .
Breast and ovarian cancers in families with BRCA2 mutations have characteristic features. Medium age of breast cancer is 52 and 53 in females and males, respectively, and 62 for ovarian cancer [31, 32].
Molecular diagnosis of BRCA2 mutations
Unlike for the BRCA1 gene, a founder effect for BRCA2 mutations was not observed with significant frequency in the Polish population . It should be noted that "de novo" mutations are rare in these groups of genes; thus the presence of founder mutations in BRCA2 is probable. As yet BRCA2 mutations should be diagnosed individually for each family by full sequencing. Since the BRCA2 gene is large - about 70 genomic kbp - the cost of sequencing of this gene is high (around 1500 euro).
In families with a detected marker of constitutional mutation the cost of analysis of two independently taken blood samples allowing exclusion or confirmation of carrier status among relatives is low - around 100 euro.
Selected rare syndromes with increased risk of breast and/or ovarian cancer
breast cancers, sarcomas, brain tumours, leukaemia, renal gland cancer
p53, high penetrance, AD
multifocal mucoid skin abnormalities, benign proliferative abnormalities of different organs, thyroid cancers, breast/ovarian cancers
colon cancers, endometrial cancers, other organ cancers including breast and ovary
MSH2, MLH1, AD
hyperpigmentation of the mouth, bowel polyps, colorectal cancers, small bowel cancers, gonadal tumours, breast cancers
Ruvalcaba-Myhre-Smith (Z. Bannayan-Riley-Ruvalcaba) syndrome
macrocephaly, bowel polyps, "café-au-lait" on penis, lymphomas, thyroid cancers, breast cancers
Heterozygotic carrier status of "ataxia telangiectasia" gene
ocular ataxia, ataxia of cerebellum and skin, hypersensitivity to radiation, different site neoplasm including breast/ovarian cancer
ATH gene carriers
increased breast cancer risk
low penetrance 20-40%, AD
gynaecomastia, cryptorchidism, extragonadal germ cell tumours, male breast cancer
47, XXY, low penetrance, <10%
Androgen receptor gene mutation
familial male breast cancer
Constitutional translocation t(11q;22q)
increased breast cancer risk
balanced translocation t(11q;22q)
Clinical management in families with high risk of breast/ovarian cancer
Special management should be applied for:
carriers of mutations of high breast/ovarian cancer risk; usually around 50% of female family members should be included in the programme;
all family members of families with HBC-ss, HBOC or HOC diagnosed definitively or with high probability according to pedigree criteria shown in Table 1, if constitutional mutations predisposing to cancer were not detected.
Special management concerns:
Contraindications for use of oral contraceptives (OC) by BRCA1 carriers aged below 25 are well documented. It was shown that OC used for 5 years by young women increase breast cancer risk by about 35% . Since in about 50% of BRCA1 carriers family history is negative it seems to be necessary to perform the BRCA1 test in every young woman who wishes to use OC. OC used by BRCA1 carriers after the age of 30 seems not to influence breast cancer risk [43–45] but shows a 50% reduction of ovarian cancer risk , so use of OC after the age of 30 appears to be justified. As yet, there are no verified data concerning the effects of OC in families not related to BRCA1 mutation. However, there are studies indicating several-fold increased breast cancer risk in OC users from families with breast cancer aggregation ; thus it seams reasonable to avoid OC in families with HBC-ss and/or HBOC.
Hormone replacement therapy (HRT)
Prophylactic oopherectomy at the age of 35-40 is the gold standard for BRCA1/2 carriers and corresponds with risk reduction for both breast and ovarian cancer. It was shown that carriers after oopherectomy, who use oestrogen HRT, show a similar protective effect as patients who do not use HRT [47, 48]. The influence of HRT in carriers without prophylactic oopherectomy is not well documented. Three-fold increased risk of breast cancer in HRT users with positive breast cancer family history was reported . Therefore, the decision about HRT use should be made with particular caution.
Long-term breast feeding is indicated in all females from families with HBC-ss, HBOC and HOC. It was shown in BRCA1 carriers that breast feeding over 18 months, counting together all pregnancies, reduces breast cancer risk - from 50-80% to 25-40% [50, 51].
Women from the general population who delivered the first child before the age of 20 are at 50% lower breast cancer risk than nulliparous women. This observation was not confirmed in women with BRCA1 or BRCA2 mutation . However, taking into consideration the fact that mutation carriers should elect prophylactic oopherectomy at age 35-40, they should not delay maternity significantly.
Literature data clearly indicate that tamoxifen reduces by about 50% the risk of ER+ breast cancers. This effect was observed in healthy women as well as in women treated for breast cancer, where tamoxifen reduced the risk of contralateral breast cancer. A protective effect of tamoxifen was also observed in BRCA1 carriers in spite of the fact that most cancers in these patients are ER-. Such an effect of tamoxifen was observed in pre- and postmenopausal women [53, 54]. According to present data it is justified to propose 5 year chemoprevention with tamoxifen to patients from families with HBC-ss, HBOC and BRCA1 mutation carriers as well after exclusion of all contraindications, especially related to clotting problems and endometrial hypertrophy.
Studies performed in our centre showed increased mutagen sensitivity in BRCA1 carriers as measured with the bleomycin test. This sensitivity may be normalized with some selenium supplements . Chemoprevention with selenium has been observed to reduce cancer risk in both humans and animals. This question should be answered in BRCA1 carriers.
Both retrospective and prospective observations of patients with BRCA1/2 mutations indicate that prophylactic adnexectomy decreases the risk of ovarian/peritoneal cancer to about 5% and breast cancer to 30-40%. Application of adnexectomy together with tamoxifen reduces breast cancer risk to about 10% in BRCA1 carriers . Therefore, in our centre adnexectomy is recommended to all BRCA1/2 carriers aged over 35. This surgery is proposed to women from families with HBC-ss, HBOC and HOC but without detected BRCA1/BRCA2 mutation only if other pathologies of the female genital tract were recorded during control examinations. About 85% of our patients accept this type of prophylaxis .
The main target of prophylactic mastectomy is reduction of breast cancer risk by removal of tissue at risk. Single cases of breast cancer can develop from the chest wall or from the axillary cave after prophylactic mastectomy. It was noted, however, that only 1% of patients from this group develop breast cancer after prophylactic surgery . It seams reasonable to offer this type of surgery to highly motivated patients with definitively diagnosed high cancer risk, especially where tumoural and mammographically dense breast glands are observed which make early diagnosis extremely difficult. At present, mastectomies with immediate reconstruction are performed most frequently. This procedure ensures a good cosmetic effect .
Scheme of control examinations in families with high breast/ovarian cancer syndromes
Age of beginning
every 6 months
every 6 months (6 months after mammography)
every 12 months
every 12 months
Female genital tract
every 12 months
every 12 months (6 months after USG)
Existing data indicate that different rules should be applied or at least considered as an option in treatment of BRCA1 carriers. They include:
radical mastectomy instead of lumpectomy followed by radiation therapy, because the risk of local recurrence in the above procedures is 1% and 8%, respectively (Narod SA, data not published);
adnexectomy not only because of prophylaxis but also because it was noted that 10-year survival is twice as high in patients after this type of treatment (Narod SA, data not published);
breast cancer chemotherapy based on schemes without taxanes ; treatment results based on schemes with cis-platinum are very promising.
Syndromes associated with genetic changes of moderately increased risk
Options of control examinations for carriers of moderate cancer risk gene mutations
Age of beginning
CHEK2 (1100delC, IVS2+1G>A, del5395), NBS1 (657del5), NOD2 (3020insC), CDKN2A (A148T)
every 6 months
every 12 months
(6 months after mammography)
BRCA2 (5972C/T), CYP1B1 (homozygote GTC)
every 12 months
every 6 months
every 12 months
(6 months after mammography)
every 12 months
every 12 months
Occurrence of breast cancer at young age is not characteristic for this kind of mutation. However, patients with this mutation demonstrate lobular type of breast cancer much more often . This cancer is difficult to diagnose using mammography; therefore in this group of patients magnetic resonance imaging (MRI) is recommended from 40 years of age. Mutation 657del5 in the NBS1 gene is associated with about 3.5-fold increased risk of breast cancer and this increase is the strongest for patients below 40 years old  and with positive cancer family history . Mutation 3020insC in the NOD2 gene is associated with breast cancer at young age (OR = 1.9). Characteristic for this mutation is ductal breast cancer with a DCIS component . This kind of cancer is more often accompanied by multiple calcifications; therefore mammography can be useful in prophylaxis of patients with mutations in the NOD2 gene. Polymorphism 5972C/T in the BRCA2 gene is also associated with increased risk of breast cancer before 40 years of age (OR = 1.4). The risk of cancer development is higher in homozygotes (OR = 4.8). This effect is observed at both young and older age . Increased risk is also observed in carriers of CDKN2A A148T (OR = 1.5) and CYP1B1 (homozygote GTC) (OR = 1.5). In these cases an increased cancer risk at young age is observed. Medical care for patients with genetic changes NBS1 (657del5), NOD2 (3020insC), BRCA2 (5972C/T), CDKN2A (A148T), and CYP1B1 (homozygote GTC) begins at 25 years. Studies on the group of patients with a family history of ovarian cancer allowed characteristic clinical features of ovarian cancers without constitutional mutations in genes BRCA1 and BRCA2 to be distinguished. Cancers in this group, unlike cases arising on the basis of BRCA1 and BRCA2 mutation, are more often diagnosed in postmenopausal (51-60 years) women and also show lower morphological grading and clinical staging. Analysis of the kind and location of cancers among relatives of examined women showed the increased frequency of ovarian cystadenoma (cystadenoma ovarii) . Cystadenomas of the ovary are benign tumours which are able to, in some cases, undergo malignant transformation into borderline malignancy tumours, and sometimes even into cancer (cystadenocarcinoma) [71, 72]. For development of this kind of tumours the following constitutional changes can predispose: NOD2 3020insC, CHEK2 I157T, CYP1B1 355T/T and DHCR7 W151X. In the group of "increased risk" there are mainly women at reproductive age (≥50 years), who being carriers of at least one of the above-mentioned molecular changes have over twofold increased risk of the development of ovarian borderline malignancy tumours (OR 2.26, P = 0.0005). Therefore for these women it should be considered to extend the screening options with an additional control examination of transvaginal USG (once a year) from 20-25 years. Early tumour detection and its surgical resection can prevent the development of ovarian cancer. Moreover, in the case of the 355T/T variant CYP1B1 gene carriers the screening options are extended with an additional control examination for MRI of the breast (once a year) for women aged 30-35 years, on account of almost 3-fold increased risk of the development of cancer of this organ (OR 2.75, P = 0.03) [73, 74]. The preventive screening is also recommended to first and second degree female relatives of patients with ovarian cystadenoma including:
control examination by using transvaginal USG (once a year), if in the patient ovarian borderline malignancy tumour and CHEK2 I157T were detected;
control breast examination using MRI (once a year) in the case of female relatives of patients with the 355T/T variant of the CYP1B1 gene and with benign ovarian tumour.
Studies on genetic predisposition to breast cancer or ovarian cystadenoma indicate the existence of multigenetic relations causing high risk of cancer development. It will probably require many years of analysis to discover them.
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