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Clinical management of women with genomic BRCA1 and BRCA2 mutations*

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Abstract

Purpose. There is increasing evidence that BRCA1 and BRCA2 associated tumors may differ from sporadic cancers. The purpose of this report is to review the current state of knowledge of BRCA1 and BRCA2, the biology of associated tumors, and possible risk reduction strategies in women with these deleterious mutations.

Design and methods. We conducted an extensive literature search of all published articles (including Medline) on preclinical data on the function of BRCA1 and BRCA2, associated tumor pathology, and the clinical management for both unaffected carriers and affected patients.

Results. BRCA1 and BRCA2 are likely to act as tumor suppressor genes, and together with RAD51 operate in a common DNA damage response pathway implicated in double-strand repair. Breast cancers associated with BRCA1 are frequently of a higher grade, steroid hormone receptor negative, and appear to have a higher proportion of atypical or typical medullary subtype. Conversely, BRCA2 associated breast cancers do not differ significantly from sporadic cancers. No special tumor phenotype has been ascribed to BRCA1 or BRCA2 associated ovarian cancers. Guidelines for risk reduction strategies for the high risk unaffected carrier have been recommended by expert panels in the USA and Europe. Lifestyle changes, multi-modality screening, chemoprevention, and prophylactic oophorectomy and mastectomy, with their possible benefits and attendant risks are described. Finally, locoregional and systemic treatment in breast and ovarian cancers associated with these mutations, and differences between these and sporadic cancers are discussed.

Conclusions. Although the incidence of breast or ovarian cancers that can be attributed to BRCA1 or BRCA2 mutations account for less than 5% of all cancers, these cancers may differ from sporadic cases in terms of tumor biology and phenotype. These differences may impact directly on clinical management of breast and ovarian cancer patients, and their relatives. Further recommendations of these patients are constantly changing as new information emerges on the clinical behavior of these cancers.

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References

  1. Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W: A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266: 66-71, 1994

    Google Scholar 

  2. Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, Collins N, Gregory S, Gumbs C, Micklem G: Identification of the breast cancer susceptibility gene BRCA2. Nature 378: 789-792, 1995

    Google Scholar 

  3. Eisinger F, Sobol H.: Comments on: current policies for surveillance and management in women at risk of breast and ovarian cancer: a survey among 16 European family cancer clinics. Eur J Cancer 35(5): 859-860, 1999

    Google Scholar 

  4. Burke W, Daly M, Garber J, Botkin J, Kahn MJ, Lynch P, McTiernan A, Offit K, Perlman J, Petersen G, Thomson E, Varricchio C: Recommendations for follow-up care of individuals with an inherited predisposition to cancer, II. BRCA1 and BRCA2: cancer genetics studies consortium. JAMA 277: 997-1003, 1997

    Google Scholar 

  5. Rahman N, Stratton MR.: The genetics of breast cancer susceptibility. Annu Rev Genet 32: 95-121, 1998

    Google Scholar 

  6. Koonin EV, Altschul SF, Bork P: BRCA-1 protein products: functional motifs. Nature 13: 266-267, 1996

    Google Scholar 

  7. Callebaut I, Mornon JP: From BRCA-1 to RAP-2: a widespread BRCT module closely associated with DNA repair. FEBS Lett 400: 25-30, 1997

    Google Scholar 

  8. Chapman MS, Verma IM: Transcriptional activation by BRCA-1. Nature 382: 678-679, 1996

    Google Scholar 

  9. Bignell G, Micklem G, Stratton MR, Ashworth A, Wooster R: The BRC repeats are conserved in mammalian BRCA2 proteins. Hum Mol Genet 6(1): 53-58, 1997

    Google Scholar 

  10. Yuan SS, Lee SY, Chen G, Song N, Tomlinson GE, Lee EY: BRCA-2 is required for ionizing radiation-induced assembly of RAD51 complex in vivo. Cancer Res 59: 3547-3551, 1999

    Google Scholar 

  11. Chen CF, Chen PL, Zhong Q, Sharp ZD, Lee WH: Expression of BRC repeats in breast cancer cells disrupts the BRCA2-Rad51 complex and leads to radiation hypersensitivity and loss of G(2)/M checkpoint control. J Biol Chem 274(46): 32931-32935, 1999

    Google Scholar 

  12. Marcus JN, Watson P, Page DL, Narod SA, Lenoir GM, Tonin P, Linder-Stephenson L, Salerno G, Conway TA, Lynch HT: Hereditary breast cancer: pathobiology, prognosis, and BRCA1 and BRCA2 gene linkage. Cancer 77(4): 697-709, 1996

    Google Scholar 

  13. Lakhani SR, Jacquemier J, Sloane JP, Gusterson BA, Anderson TJ, van de Vijver MJ, Farid LM, Venter D, Antoniou A, Storfer-Isser A, Smyth E, Steel CM, Haites N, Scott RJ, Goldgar D, Neuhausen S, Daly PA, Ormiston W, McManus R, Scherneck S, Ponder BA, Ford D, Peto J, Stoppa-Lyonnet D, Easton DF: Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. J Natl Cancer Inst 90: 1138-1145, 1998

    Google Scholar 

  14. Noguchi S, Kasugai T, Miki Y, Fukutomi T, Emi M, Nomizu T.: Clinicopathologic analysis of BRCA1-or BRCA2-associated hereditary breast carcinoma in Japanese women. Cancer 85: 2200-2205, 1999

    Google Scholar 

  15. Phillips K-A, Nichol K, Ozcelik H, Knight J, Done SJ, Goodwin PJ, Andrulis IL: Frequency of p53 mutations in breast carcinomas from Ashkenazi Jewish carrriers of BRCA1 mutations. J Natl Cancer Inst 91(5): 469-473, 1999

    Google Scholar 

  16. Loman N, Johannsson O, Bendahl PO, Borg A, Feno M, Olsson H: Steroid receptors in hereditary breast carcinomas associated with BRCA-1 or BRCA-2 mutations or unknown susceptibility genes. Cancer 83: 310-319, 1998

    Google Scholar 

  17. Ramus SJ, Bobrow LG, Pharoah PD, Finnigan DS, Fishman A, Altaras M, Harrington PA, Gayther SA, Ponder BA, Friedman LS: Increased frequency of TP53 mutations in BRCA1 and BRCA2 ovarian tumours. Genes Chromosomes Cancer 25(2): 91-96, 1999

    Google Scholar 

  18. Verhoog LG, Brekelmans CTM, Seynaeve C, Dahmen G, van Geel AN, Bartels CC, Tilanus-Linthorst MM, Wagner A, Devilee P, Halley DJ, van den Ouweland AM, Meijers-Heijboer EJ, Klijn JG: Survival in hereditary breast cancer associated with germline mutations of BRCA2. J Clin Oncol 17: 3396-3402, 1999

    Google Scholar 

  19. Robson M, Rajan P, Rosen PP, Gilewski T, Hirschaut Y, Pressman P, Haas B, Norton L, Offit K: BRCA-associated breast cancer: absence of a characteristic immunophenotype. Cancer Res 58: 1839-1842, 1998

    Google Scholar 

  20. Lynch BJ, Holden JA, Buys SS, Neuhausen SL, Gaffney DK: Pathobiologic characteristics of hereditary breast cancer. Hum Pathol 29(10): 1140-1144, 1998

    Google Scholar 

  21. Crook T, Crossland S, Crompton M, Osin P, Gusterson B: p53 mutations in BRCA1-associated familial breast cancer. Lancet 350: 638-639, 1997

    Google Scholar 

  22. Gretarsdottir S, Thorlacius S, Valgardsdottir R, Gudlaugsdottir S, Sigurdsson S, Steinarsdottir M, Jonasson JG, Anamthawat-Jonsson K, Eyfjord JE: BRCA2 and p53 mutations in primary breast cancer in relation to genetic instability. Cancer Res 58: 859-862, 1998

    Google Scholar 

  23. Brugarolas J, Jacks T: Double indemnity: p53, BRCA and cancer. p53 mutation partially rescues developmental arrest in BRCA1 and BRCA2 null mice, suggesting a role for familial breast cancer genes in DNA damage repair. Nat Med 3(7): 721-722, 1997

    Google Scholar 

  24. Tirkkonen M, Johannsson O, Agnarsson BA, Olsson H, Ingvarsson S, Karhu R, Tanner M, Isola J, Barkardottir RB, Borg A, Kallioniemi OP: Distinct somatic genetic changes associated with tumor progression in carriers of BRCA1 and BRCA2 germ-line mutations. Cancer Res 57: 1222-1227, 1997

    Google Scholar 

  25. Rhei E, Bogomolniy F, Federici MG, Maresco DL, Offit K, Robson ME, Saigo PE, Boyd J: Molecular genetic characterization of BRCA1-and BRCA2-linked hereditary ovarian cancers. Cancer Res 58: 3193-3196, 1998

    Google Scholar 

  26. Schorge JO, Muto MG, Welch WR, Bandera CA, Rubin SC, Bell DA, Berkowitz RS, Mok SC: Molecular evidence for multifocal papillary serous carcinoma of the peritoneum in patients with germline BRCA1 mutations. J Natl Cancer Inst 90(11): 841-845, 1998

    Google Scholar 

  27. Rubin SC, Benjamin I, Behbakht K, Takahashi H, Morgan MA, LiVolsi VA, Berchuck A, Muto MG, Garber JE, Weber BL, Lynch HT, Boyd J: Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1. N Engl J Med 335: 1413-1416, 1996

    Google Scholar 

  28. Ansquer Y, Gautier C, Fourquet A, Asselain B, Stoppa-Lyonnet D: Survival in early-onset BRCA1 breast-cancer patients: Institute Curie Breast Cancer Group. Lancet 352(9127): 541, 1998

    Google Scholar 

  29. Johannsson OT, Ranstam J, Borg A, Olsson H: Survival of BRCA1 breast and ovarian cancer patients: a population-based study from southern Sweden. J Clin Oncol 16: 397-344, 1998

    Google Scholar 

  30. Foulkes WD, Chappuis PO, Wong N, Brunet JS, Vesprini D, Rozen F: Primary node negative breast cancer in BRCA1 mutation carriers has a poor outcome. Ann Oncol 11(3): 307-313, 2000

    Google Scholar 

  31. Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, Bishop DT, Weber B, Lenoir G, Chang-Claude J, Sobol H, Teare MD, Struewing J, Arason A, Scherneck S, Peto J, Rebbeck TR, Tonin P, Neuhausen S, Barkardottir R, Eyfjord J, Lynch H, Ponder BA, Gayther SA, Zelada-Hedman M: Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families: The Breast Cancer Linkage Consortium. Am J Hum Genet 62(3): 676-689, 1998

    Google Scholar 

  32. Struewing JP, Hartge P, Wacholder S, Baker SM, Berlin M, McAdams M, Timmerman MM, Brody LC, Tucker MA: The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336(20): 1401-1408, 1997

    Google Scholar 

  33. Daly M: NCCN practice guidelines-genetics/familial highrisk cancer screening. Oncology 13: 161-183, 1999

    Google Scholar 

  34. Hunter DJ, Spiegelman D, Adami HO, Beeson L, van den Brandt PA, Folsom AR, Fraser GE, Goldbohm RA, Graham S, Howe GR: Cohort studies of fat intake and the risk of breast cancer-a pooled analysis. N Engl J Med 334: 356-361, 1996

    Google Scholar 

  35. Howe GR, Hirohata T, Hislop G, Iscovich JM, Yuan JM, Katsouyanni K: Dietary factors and the risk of breast cancer: combined analysis of 12 case-control studies. J Natl Cancer Inst 82: 561-569, 1990

    Google Scholar 

  36. Wu AH, Ziegler RG, Nomura AM, West DW, Kolonel LN, Horn-Ross PL, Hoover RN, Pike MC: Soy intake and the risk of breast cancer in Asians and Asian Americans. Am J Clin Nutri 68: 1437-1443, 1998

    Google Scholar 

  37. Ingram D, Sanders K, Kolybaba M, Lopez D: Case-control study of phyto-oestrogens and breast cancer. Lancet 350: 990-994, 1997

    Google Scholar 

  38. Viel JF, Perarnau JM, Challier B, Faivre-Nappez I: Alcoholic calories, red wine consumption and breast cancer among premenopausal women. Eur J Epidemiol 13(6): 639-643, 1997

    Google Scholar 

  39. La Vecchia C, Negri E, Parazzini F, Boyle P, Fasoli M, Gentile A: Alcohol and breast cancer: update from an Italian casecontrol study. Eur J Cancer Clin Oncol 25(12): 1711-1717, 1989

    Google Scholar 

  40. Richardson S, de Vincenzi I, Pujol H, Gerber M: Alcohol consumption in a case-control study of breast cancer in southern France. Int J Cancer 44: 84-89, 1989

    Google Scholar 

  41. Thune I, Brenn T, Lund E, Gaard M: Physical activity and the risk of breast cancer. N Engl J Med 336: 1269-1275, 1997

    Google Scholar 

  42. Carpenter CL, Ross RK, Paganini-Hill A, Bernstein L: Lifetime exercise activity and breast cancer risk among postmenopausal women. Br J Cancer 80(11): 1852-1858, 1999

    Google Scholar 

  43. Brunet JS, Ghadirian P, Rebbeck TR, Lerman C, Garber JE, Tonin PN, Abrahamson J, Foulkes WD, Daly M, Wagner-Costalas J, Godwin A, Olopade OI, Moslehi R, Liede A, Futreal PA, Weber BL, Lenoir GM, Lynch HT, Narod SA: Effect of smoking on breast cancer in carriers of mutant BRCA1 or BRCA2 genes. J Natl Cancer Inst 90(10): 761-766, 1998

    Google Scholar 

  44. Narod SA, Goldgar D, Cannon-Albright L, Weber B, Moslehi R, Ives E, Lenoir G, Lynch H: Risk modifiers in carriers of BRCA1 mutations. Int J Cancer 64(6): 394-398, 1995

    Google Scholar 

  45. Jernstrom H, Lerman C, Ghadirian P, Lynch HT, Weber B, Garber J, Daly M, Olopade OI, Foulkes WD, Warner E, Brunet JS, Narod SA: Pregnancy and risk of early breast cancer in carriers of BRCA1 and BRCA2. Lancet 354: 1846-1850, 1999

    Google Scholar 

  46. Elmore JG, Barton MB, Moceri VM, Polk S, Arena PJ, Fletcher SW.: Ten-year risk of false positive screening mammograms and clinical breast examinations. N Engl J Med 338(16): 1089-1096, 1998

    Google Scholar 

  47. Scully R, Chen J, Ochs RL, Keegan K, Hoekstra M, Feunteun J, Livingston DM: Dynamic changes of BRCA1 subnuclear locations and phosphorylation state are initiated by DNA damage. Cell 90(3): 425-435, 1997

    Google Scholar 

  48. Thomas DB, Gao DL, Self SG, Allison CJ, Tao Y, Mahloch J, Ray R, Qin Q, Presley R, Porter P: Randomized trial of breast self-examination in Shanghai: methodology and preliminary results. J Natl Cancer Inst 89(5): 355-365, 1997

    Google Scholar 

  49. Fisher B, Costantino J, Wickerham DL, Redmond C, Kavanah MT, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark N: Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90: 1371-1388, 1998

    Google Scholar 

  50. Veronesi U, Maisonneuve P, Costa A, Sacchini V, Maltoni C, Robertson C, Rotmensz N, Boyle P: Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women, Italian Tamoxifen Prevention Study. Lancet 352(9122): 93-97, 1998

    Google Scholar 

  51. Powles T, Eeles R, Ashley S, Easton D, Chang J, Dowsett M, Tidy A, Viggers J, Davey J: Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet 352(912): 98-101, 1998

    Google Scholar 

  52. MacMahon B, Feinlieb M.: Breast cancer in relation to nursing and menopausal history. J Natl Cancer Inst 24: 733-753, 1960

    Google Scholar 

  53. Pike MD, Spicer DV: The chemoprevention of breast cancer by reducing sex steroid exposure: perspectives from epidemiology. J Clin Oncol 17G: 26-36, 1993

    Google Scholar 

  54. Lippman SM, Benner SE, Hong WK: Retinoid chemoprevention studies in upper aerodigestive tract and lung carcinogenesis. Cancer Res 54(7 Suppl): 2025s-2028s, 1994 (Review)

    Google Scholar 

  55. Veronesi U, De Palo G, Marubini E, Costa A, Formelli F, Mariani L, Decensi A, Camerini T, Del Turco MR, Di Mauro MG, Muraca MG, Del Vecchio M, Pinto C, D'Aiuto G, Boni C, Campa T, Magni A, Miceli R, Perloff M, Malone WF, Sporn MB: Randomized trial of fenretinide to prevent second breast malignancy in women with early breast cancer. J Natl Cancer Inst 91(21): 1847-1856, 1999

    Google Scholar 

  56. Yee D, McGuire SE, Brunner N, Kozelsky TW, Allred DC, Chen SH, Woo SL: Adenovirus-mediated gene transfer of herpes simplex virus thymidine kinase in an ascites model of human breast cancer. Hum Gene Ther 7(10): 1251-1257, 1996

    Google Scholar 

  57. Love SM, Barsky SH.: Breast-duct endoscopy to study stages of cancerous breast disease. Lancet 348(9033): 997-999, 1996

    Google Scholar 

  58. Hartmann LC, Schaid DJ, Woods JE, Crotty TP, Myers JL, Arnold PG, Petty PM, Sellers TA, Johnson JL, McDonnell SK, Frost MH, Jenkins RB: Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med 340(2): 77-84, 1999

    Google Scholar 

  59. Hartmann LC, Schaid D, Sellers T, McDonnell S, Woods J, Sitta D: Bilateral prophylactic mastectomy (PM) in BRCA1/2 mutation carriers. Proc Am Assoc Cancer Res 2000

  60. Humphrey LJ: Subcutaneous mastectomy is not a prophylaxis against carcinoma of the breast: opinion or knowledge? Am J Surg 145(3): 311-312, 1983

    Google Scholar 

  61. Stefanek ME, Helzlsouer KJ, Wilcox PM, Houn F: Predictors of and satisfaction with bilateral prophylactic mastectomy. Prev Med 24(4): 412-419, 1995

    Google Scholar 

  62. Rebbeck TR, Levin AM, Eisen A, Snyder C, Watson P, Cannon-Albright L, Isaacs C, Olopade O, Garber JE, Godwin AK, Daly MB, Narod SA, Neuhausen SL, Lynch HT, Weber BL: Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers. J Natl Cancer Inst 91(17): 1475-1479, 1999

    Google Scholar 

  63. Jacobs IJ, Skates SJ, MacDonald N, Menon U, Rosenthal AN, Davies AP, Woolas R, Jeyarajah AR, Sibley K, Lowe DG, Oram DH: Screening for ovarian cancer: a pilot randomised controlled trial. Lancet 353(9160): 1207-1210, 1999

    Google Scholar 

  64. Narod SA, Risch H, Moslehi R, Dorum A, Neuhausen S, Olsson H, Provencher D, Radice P, Evans G, Bishop S, Brunet JS, Ponder BA: Oral contraceptives and the risk of hereditary ovarian cancer, Hereditary Ovarian Cancer Clinical Study Group. N Engl J Med 339(7): 424-428, 1998

    Google Scholar 

  65. The reduction in risk of ovarian cancer associated with oral contraceptive use: The Cancer and Steroid Hormone Study of the Centers for disease control and the National Institute of Child Health and Human Development. N Engl J Med 316(11): 650-655, 1987

  66. Grabrick DM, Hartmann LC, Cerhan JR, Vierkant RA, Therneau TM, Vachon CM: Risk of breast cancer with oral contraceptive use in women with a family history of breast cancer. JAMA 284(14): 1791-1798, 2000

    Google Scholar 

  67. Ursin G, Henderson BE, Haile RW, Pike MC, Zhou N, Diep A, Bernstein L: Does oral contraceptive use increase the risk of breast cancer in women with BRCA1/BRCA2 mutations more than in other women? Cancer Res 57(17): 3678-3681, 1997

    Google Scholar 

  68. Piver MS: Prophylactic, oophorectomy, and ovarian cancer mortality. Cancer Prev 1-12, 1992

  69. Struewing JP, Watson P, Easton DF, Ponder BA, Lynch HT, Tucker MS: Prophylactic oophorectomy in inherited breast/ovarian cancer families. J Natl Cancer Inst Monogr (17): 33-35, 1995

    Google Scholar 

  70. Garber JE, Isaacs C, Daly MB, Neuhausen SL, Rebbeck TR: Ovarian cancer risk reduction after bilateral prophylactic oophorectomy (BPO) in BRCA1 and BRCA2 mutation carriers. Proc Am Soc Human Gen 2000

  71. Pierce LJ, Strawderman M, Narod SA, Oliviotto I, Eisen A, Dawson L, Gaffney D, Solin LJ, Nixon A, Garber J, Berg C, Isaacs C, Heimann R, Olopade OI, Haffty B, Weber BL: No deleterious effects of radiotherapy in women who are heterozygote for a BRCA-1 or BRCA-2 mutation following breast-conserving therapy. Proc Am Soc Clin Oncol 18: 86A, 1999

    Google Scholar 

  72. Turner BC, Harrold E, Matloff E, Smith T, Gumbs AA, Beinfield M, Ward B, Skolnick M, Glazer PM, Thomas A, Haffty BG: BRCA1/BRCA2 germline mutations in locally recurrent breast cancer patients after lumpectomy and radiation therapy: implications for breast-conserving management in patients with BRCA1/BRCA2 mutations. J Clin Oncol 17(10): 3017-3024, 1999

    Google Scholar 

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  1. Department of Medicine, Baylor-Methodist Breast Care Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA

    Jenny Chang & Richard M. Elledge

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Chang, J., Elledge, R.M. Clinical management of women with genomic BRCA1 and BRCA2 mutations*. Breast Cancer Res Treat 69, 101–113 (2001). https://doi.org/10.1023/A:1012203917104

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