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The pathology of familial breast cancer: Clinical and geneticcounselling implications of breast cancer pathology


Approximately 5% of all breast cancers are due to one of the high-risk breast cancer genes BRCA1 and BRCA2, or possibly to a third or fourth moderate- to high-risk gene(s). A further proportion of cases arise in the presence of a less striking family history, with later average age at onset and lower penetrance: familial breast cancer. Bilaterality is a recognized feature of hereditary breast cancer. Cancers often present at an early age, with the contralateral risk high within 10 years. Proof that bilateral malignancies are separate primaries can be difficult histologically, however, especially within 3 years. The recent finding of specific pathological features related to BRCA1 and, to a lesser extent, BRCA2 mutations means that, in addition to bilaterality and family history, a pathological element can be entered into the risk calculation for the presence of BRCA1/BRCA2 mutations. This will facilitate the targeting of mutation testing to families in which a positive result is most likely, and may subsequently influence the clinical management of these families.

Breast cancer genetics

A number of genes have been identified during the past 10 years which, when inherited in a mutant form, confer a high lifetime risk for breast cancer and for a spectrum of other cancers. These genes are not common and together are estimated to occur in a mutated form in about one in 300 individuals in the general population [1*,2], and to account for about 5% of all breast cancers. The proportion of young breast cancers accounted for by these high-risk genes is, however, considerably higher [3]. In addition to these high-risk susceptibility genes, there are also likely to be a number of lower penetrance, more frequently occurring gene mutations that increase breast cancer risk. These probably interact significantly with epidemiological risk factors [4]. Few such genes or polymorphisms have been identified as yet.

The breast cancer genes

BRCA1 was mapped to chromosome 17q in 1990 [5] and the genetic sequence was published in 1994 [6], simultaneously with a report of the localization of a second major susceptibility gene BRCA2 [7]. BRCA2 was cloned in 1995 [8]. These genes are both large and mutation analysis is expensive and time consuming. Nonetheless, in families with a high chance of a genetic predisposition, genetic testing is offered in most Western genetics centres. Thus, an increasing number of young women with a strong family history of breast and ovarian cancer are undergoing presymptomatic genetic testing.

Somatic mutations in the TP53 gene are extremely common in all types of cancer. Inherited germline mutations are, however, rare. The Li-Fraumeni syndrome (LFS) represents the striking pattern of childhood malignancy (typically soft tissue and osteosarcomas, gliomas or adrenocortical carcinoma) and very early onset breast cancer (50% of female gene carriers have developed breast cancer by 30 years of age). Over 70% of classical LFS families have inherited TP53 mutations [9*]. There is good in-vitro evidence to suggest that patients with LFS have an abnormal response to low-dose radiation with defective apoptosis [10]. Recognition of this syndrome is therefore important, not least because it has implications for breast-screening methods.

Other recently discovered genes that confer an increase in risk of breast cancer and are associated with bilateral benign and malignant breast disease are Cowden's disease (due to mutations in the PTEN gene [11]) and Peutz-Jehger syndrome (PJS; due to mutations in CDNK4 [12]). Both are rare, and the lifetime risk of breast cancer is probably less than 35%. Both these conditions have a distinct clinical phenotype with a diagnosis possible on clinical grounds (mucosal pigmentation in PJS; macrocephaly, scrotal tongue and thyroid tumours in Cowden's disease) and on pathology of skin and gut tumours (typical hamartomas of the gut in PJS and trichilemmomas in Cowden's disease).

It is difficult to predict whether BRCA1 or BRCA2 mutations are present in most families with multiple cases of breast cancer. The presence of two or more ovarian cancers in addition to two or more breast cancers diagnosed before the age of 60 years gives at least a 90% likelihood of BRCA1 mutation, and male breast cancer plus three or more breast cancers diagnosed before the age of 60 years gives an 80% risk of BRCA2 [13]. These particular families, however, represent less than 0.5% of all breast cancer and probably less than 10% of all BRCA1/BCRA2 families. In particular, families with only two or three breast cancers diagnosed before the age of 60 years have a relatively small risk of a BRCA1/BRCA2 mutation, and the majority of the hereditary element is due to other, as yet unidentified, genes [13]. Therefore, information from the breast cancer pathology may help prioritize those families in which genetic screening of BRCA1/BRCA2 would be most useful.

Pathology of hereditary breast cancer

Hereditary breast cancer has some interesting biological differences compared with apparently sporadic cancer. In breast malignancies from patients with a BRCA1 mutation, a greater proportion are high grade and histologically medullary or atypical medullary in type [14,15*].

Therefore, in individuals with bilateral medullary/atypical medullary cancer, the probability of BRCA1 mutation should be very high. This will need to be confirmed by further studies. At the present time, no other histopathological type is associated with mutations in particular susceptibility genes. Nonetheless, finding bilateral breast cancers or multiple primary tumours will increase the chance of hereditary disease.

Both lobular carcinoma in situ (LCIS) and atypical hyperplasia have been associated with family histories of breast cancer [16,17]. The 10 year risk of invasive disease in association with family history is approximately 40% [17]. Skolnick et al [16] suggested that persons with LCIS were more likely to have a mother or sister with breast disease than with other tumour types. The Breast Cancer Linkage Consortium [15*], however, demonstrated that LCIS was less common in carriers of BRCA1 and BRCA2 mutations than in sporadic control individuals, although this did not reach formal statistical significance. Skolnick et al [16] did not find a significant statistical association between ductal carcinoma in situ (DCIS) and family history. This was supported by the Breast Cancer Linkage Consortium data, which found fewer cases of DCIS among BRCA1 mutation carriers than among control individuals. The rate of DCIS in BRCA2 mutation carriers was similar to that in sporadic control individuals, however. It may be that proliferative breast disease is a marker for BRCA3/BRCA4.

The evidence from histological studies for the association of specific types of tumour with BRCA1 and BRCA2 mutations will allow a directed approach to genetic testing of breast cancer families.

The survival of women with breast cancers with known mutations in BRCA1/BRCA2 is controversial. Early reports based on families linked to BRCA1 [18] suggested that the survival for these women was significantly better than that in matched individuals with sporadic tumours. This study had a survival bias, however; in order to ascertain large families for genetic linkage, a number of women within the family need to survive. Other studies have suggested that the survival is worse in BRCA1 and BRCA2 mutation carriers [19], or the same [20,21]. A more recent study [22] of Ashkenazi Jews with mutations in BRCA1/BRCA2 demonstrated that carriers did not seem to have either a better or worse prognosis. Larger prospective studies are needed to answer fully the question of survival among this group of women with breast cancer.

Genetic testing

A number of groups have reported on the likelihood of finding BRCA1 and to a lesser extent BRCA2 mutations in certain given situations with different family histories [23,24]. The new information from breast pathologists will almost certainly alter the approach. Although the chances of finding a BRCA1 mutation in an individual with a sporadic breast cancer who is aged under 50 years is small [25], this would alter significantly if medullary features were found, particularly in the presence of a family history of breast or ovarian cancer. Most genetic testing occurs in the context of an unaffected woman seeking advice about her risks of breast cancer. Therefore, the pathology of the breast cancers in her relatives will be relevant. Finding a histology report with medullary features or that all the breast cancers in the family were oestrogen receptor negative and grade 3 would heighten the chance of finding a mutation in the family, thus enabling further management guidance of the individual at risk. Even if the woman does not want to know her own BRCA1/BRCA2 status [26*], she may still want to take advantage of ovarian screening because she would be at half the carrier risk for ovarian cancer of 20-60% [2].

Breast cancer management

Once breast cancer develops in an individual, appropriate management of that cancer is the primary consideration. Because many of these patients are young and present with early cancers, breast conservation is in many cases technically possible. Wide local excision and axillary node sampling (at least) with adjuvant radiotherapy might be expected to produce equivalent results to simple mastectomy if this disease is similar in all respects to sporadic breast cancer. For a woman with either a proved or suspected genetic susceptibility, the chance of recurrence must take into account the background susceptibility of the remaining breast tissue. This includes the risk of a new primary in the contralateral breast. In order to discuss this, an estimate of the risk involved is required. Because familial cancers are more likely to be multifocal and bilateral, the risk of a new primary on the treated side is likely to be high without adjuvant therapy. There are very little data on the conservative management of BRCA1/BRCA2 mutation carriers compared with those with sporadic disease, although the outcome of breast conservation in a small number of hereditary versus sporadic early age breast cancers in an American cohort [27] has been reported. At present, there is no clear contraindication to breast conservation for the affected breast.

Management of the contralateral breast

The risk to the contralateral breast for a woman with breast cancer and a hereditary predisposition approaches 50% at 10 years [28]. The greatest chance of recurrence of breast cancer, either locoregional or metastatic, is in the first 2 years after diagnosis. Given the high contralateral risk, many women with a BRCA1/BRCA2 mutation (or a high risk for carrying a mutation) may opt for prophylactic removal of the contralateral breast in addition to mastectomy for the ipsilateral side. A further option is close surveillance of the remaining breast tissue. Screening for early breast cancer is of uncertain benefit in terms of a clear reduction in mortality, however [29,30], although early cancers can undoubtedly be detected [31,32,33]. Conventional mammographic screening may be less sensitive in the younger breast [30], but this remains unclear.

Screening for breast cancer

Whereas screening by mammography has been accepted in the UK for women over the age of 50 years [34], screening under this age is still controversial. A number of studies [31,33] suggest that screening women with a family history of breast or ovarian cancer is of use. If a woman has bilateral medullary carcinoma of the breast, even in the absence of any further family history, it becomes likely that the malignancy is due to a BRCA1 mutation. Unaffected women in this type of family should then be offered mammographic screening. Because tumours associated with BRCA1 mutations are highly proliferative, screening intervals would have to be adjusted to avoid interval cancers. The pathology of breast cancers can therefore be used to direct clinical screening of families as well as genetic screening.

Further studies

We would suggest that the following studies should be undertaken in the future in order to clarify further the correlation between breast cancer pathology and family history/BRCA mutations: (1) a long term prospective study of the pathology of breast tumours in families with known BRCA mutations; (2) analysis of BRCA1 in an unselected series of medullary carcinoma; (3) assessment of families with proliferative breast disease for the potential involvement of future BRCA genes; and (4) The inclusion of pathology data into the risk evaluation equation in families already tested for BRCA1/ BRCA2 mutations.


Although options for women diagnosed with breast cancer in the presence of a family history may seem limited and the evidence to support each option relatively thin, many women recently diagnosed are now requesting genetic tests to guide their decisions and those of their family. The pathology of their breast cancer may give further useful information in deciding which samples represent a high priority for genetic testing.


  1. Claus EB, Risch NJ, Thompson WD: Age at onset as an indicator of familial risk of breast cancer. Am J Epidemiol. 1990, 131: 961-972.

    CAS  PubMed  Google Scholar 

  2. Ford D, Easton DF, Peto J: Estimates of the gene frequency of BRCA1 and its contribution to breast and ovarian cancer incidence. Am J Hum Genet. 1995, 57: 1457-1462.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Langston AA, Malone KE, Thompson JD, Daling JR, Ostrander EA: BRCA1 mutations in a population-based sample of young women with breast cancer. N Engl J Med. 1996, 334: 137-142. 10.1056/NEJM199601183340301.

    Article  CAS  PubMed  Google Scholar 

  4. Easton D: Breast cancer genes-what are the real risks? . Nature Genet. 1997, 16: 210-211.

    Article  CAS  PubMed  Google Scholar 

  5. Hall JM, Lee MK, Newman B, et al: Linkage of early-onset familial cancer to chromosme 17q21. Science. 1990, 250: 1684-1689.

    Article  CAS  PubMed  Google Scholar 

  6. Miki Y, Swensen J, Shattuck-Eidens D, et al: A strong candidate for the breast and ovarian cancer susceptibility gene, BRCA1. Science. 1994, 266: 66-71.

    Article  CAS  PubMed  Google Scholar 

  7. Wooster R, Neuhausen SL, Mangion J, et al: Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science. 1994, 265: 2088-2090.

    Article  CAS  PubMed  Google Scholar 

  8. Wooster R, Bignell G, Lancaster J, et al: Identification of the breast cancer gene BRCA2. Nature. 1995, 378: 789-791. 10.1038/378789a0.

    Article  CAS  PubMed  Google Scholar 

  9. Varley JM, Evans DGR, Birch JM: Li-Fraumeni Syndrome: a molecular and clinical review. Br J Cancer. 1997, 76: 1-14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Boyle JM, Greaves MJ, Camplejohn RS, et al: Radiation induced G(1) arrest is not defective in fibroblasts from Li-Fraumeni families without TP53 mutations. Br J Cancer. 1999, 79: 1657-1664. 10.1038/sj.bjc.6690265.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Marsh DJ, Coulon V, Lunetta KL, et al: Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutations. Hum Mol Genet. 1998, 7: 507-516. 10.1093/hmg/7.3.507.

    Article  CAS  PubMed  Google Scholar 

  12. Hemminki A, Markie D, Tomlinson I, et al: A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature. 1998, 391: 184-187. 10.1038/34432.

    Article  CAS  PubMed  Google Scholar 

  13. Ford D, Easton DF, Stratton M, et al: Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet. 1998, 62: 676-689. 10.1086/301749.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Armes JE, Egan AJM, Southey MC, et al: The histologic phenotypes of breast carcinoma occuring before age 40 years in women with and without BRCA1 and BRCA2 germline mutations. Cancer. 1998, 83: 2335-2345. 10.1002/(SICI)1097-0142(19981201)83:11<2335::AID-CNCR13>3.3.CO;2-E.

    Article  CAS  PubMed  Google Scholar 

  15. Breast Cancer Linkage Consortium : Pathology of familial breast cancer: differences between cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Lancet. 1997, 349: 1505-1510. 10.1016/S0140-6736(96)10109-4.

    Article  Google Scholar 

  16. Skolnick MH, Cannon-Albright L, Goldgar DE, et al: Inheritance of proliferative breast disease in breast cancer kindreds. Science. 1990, 250: 1715-1720.

    Article  CAS  PubMed  Google Scholar 

  17. Dupont WD, Page DL: Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med. 1985, 312: 146-151.

    Article  CAS  PubMed  Google Scholar 

  18. Porter DE, Cohen BB, Wallace MR, et al: Breast cancer incidence, penetrance and survival in probable carriers of BRCA1 gene mutation families linked to BRCA1 on chromosome 17q12-21. Br J Surg . 1994, 81: 1512-1515.

    Article  CAS  PubMed  Google Scholar 

  19. Foulkes W, Wong N, Brunet JS, et al: Germ-line BRCA1 mutation is an adverse prognostic factor in Ashkenazi Jewish women with breast cancer. Clin Cancer Res. 1997, 3: 2465-2469.

    CAS  PubMed  Google Scholar 

  20. Verhoog LC, Brekelmans CTM, Seynaeve C, et al: Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1. Lancet. 1998, 351: 316-321. 10.1016/S0140-6736(97)07065-7.

    Article  CAS  PubMed  Google Scholar 

  21. Marcus JN, Watson P, Page DL: Hereditary breast cancer. Pathobiology, prognosis and BRCA1 and BRCA2 linkage. Cancer. 1996, 77: 697-709. 10.1002/(SICI)1097-0142(19960215)77:4<697::AID-CNCR16>3.0.CO;2-W.

    Article  CAS  PubMed  Google Scholar 

  22. Lee JS, Wacholder S, Struewing JP, et al: Survival after breast cancer in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst. 1999, 91: 259-263. 10.1093/jnci/91.3.259.

    Article  CAS  PubMed  Google Scholar 

  23. Frank TS, Manley SA, Olufunmilayo I, et al: Sequence analysis of BRCA1 and BRCA2: correlations of mutations with family history and ovarian cancer risk. J Clin Oncol. 1998, 16: 2417-2425.

    CAS  PubMed  Google Scholar 

  24. Chang-Claude J, Dong J, Schmidt S, et al: Using gene carrier probability to select high risk families for identifying germline mutations in breast cancer susceptibility genes. J Med Genet. 1998, 35: 116-121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Peto J, Collins N, Barfoot R, et al: Prevalence of BRCA1 and BRCA2 gene mutations in patients with early onset breast cancer. J Natl Cancer Inst. 1999, 91: 943-949. 10.1093/jnci/91.11.943.

    Article  CAS  PubMed  Google Scholar 

  26. Lerman C, Narod S, Schulman K, et al: BRCA1 testing in families with hereditary breast-ovarian cancer: a prospective study of patient decision making and outcomes. JAMA. 1996, 275: 1885-1892. 10.1001/jama.275.24.1885.

    Article  CAS  PubMed  Google Scholar 

  27. Chabner E, Nixon A, Gelman R, et al: Family history and treatment outcomes in young women after breast-conserving surgery and radiation therapy for early-stage breast cancer. J Clin Oncol . 1998, 16: 2045-2051.

    CAS  PubMed  Google Scholar 

  28. Easton DF, Ford D, Bishop DT: Breast and ovarian cancer incidence in BRCA1-mutation carriers. Am J Hum Genet. 1995, 56: 265-271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Tabár L, Larsson LG, Anderson I, et al: Breast-cancer screening with mamography in women aged 40-49 years. Int J Cancer. 1996, 68: 693-699. 10.1002/(SICI)1097-0215(19961211)68:6<693::AID-IJC1>3.3.CO;2-P.

    Article  Google Scholar 

  30. Dickersin K: Breast screening inwomen aged 40-49 years: what next?. Lancet. 1999, 353: 1896-1897. 10.1016/S0140-6736(99)90074-0.

    Article  CAS  PubMed  Google Scholar 

  31. Lalloo F, Boggis CRM, Evans DGR, et al: Screening by mammography, women with a family history of breast cancer. Eur J Cancer. 1998, 34: 937-940. 10.1016/S0959-8049(98)00005-7.

    Article  CAS  PubMed  Google Scholar 

  32. Möller P, Maehle L, Heimdal K, et al: Prospective findings in breast cancer kindreds: annual incidence rates according to age, stage at diagnosis, mean sojourn time, and incidence rates for contralateral cancer. Breast. 1998, 7: 55-59. 10.1016/S0960-9776(98)90053-4.

    Article  Google Scholar 

  33. Kollias J, Sibbering DM, Blamey RW, et al: Screening women aged less than 50 years with a family history of breast cancer. Eur J Cancer. 1998, 34: 878-883. 10.1016/S0959-8049(97)00365-1.

    Article  CAS  PubMed  Google Scholar 

  34. Forrest APM: . Breast Cancer Screening: Report to the Health Ministers of England, Wales, Scotland and Northern Ireland. London: HMSO. 1986

    Google Scholar 

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Lalloo, F., Evans, D.G.R. The pathology of familial breast cancer: Clinical and geneticcounselling implications of breast cancer pathology. Breast Cancer Res 1, 48 (1999).

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