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Genetic Testing Today

  • Breast Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

The commercial introduction of next-generation sequencing has made it possible to test for mutations in all known or suspected breast cancer predisposition genes in one panel, at one time, for about the same cost as a BRCA gene test. Clinicians are increasingly presented with the challenge of advising patients with mutations in rare breast cancer predisposition genes.

Methods

Literature review and personal experience with panel tests.

Results

Panel tests are more likely to identify a variant of uncertain clinical significance than a deleterious mutation. In addition, not all of the genes included in panel tests are unequivocally linked to increased breast cancer risk, and for most genes the penetrance is highly variable, making it difficult to translate a specific mutation into an absolute breast cancer risk. The three-generation cancer family history should be used to select truly high-risk families for panel testing, and then referred to again when the results are received in order to guide risk-management decisions. Knowing a breast cancer patient’s mutation status can influence decisions about local–regional and systemic therapy, but turnaround times for many tests are still too long to incorporate them into the initial evaluation of a new breast cancer.

Conclusion

The commercialization of next-generation sequencing has the potential to greatly enhance the identification and management of individuals with an inherited predisposition to breast cancer. A period of uncertainty is anticipated before the full potential of this new technology is realized.

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References

  1. Lebert H. Traite Pratique des Maladies Cancereuses. Paris: Librarie de L’Academie Nationale de Medecine;1851:134–135.

    Google Scholar 

  2. Broca P. Traité des tumeurs. Paris: P. Asselin; 1866: pp. 150–152.

    Google Scholar 

  3. Mendel G. Versuche über Pflanzenhybriden Verh Naturforsch Ver Brünn. 1865;4:3–47.

    Google Scholar 

  4. Miescher F. Ueber die chemische Zusammensetzung der Eiterzellen. Med Chem Unters. 1871;4:441–460.

    Google Scholar 

  5. Avery OT, MacLeod CM, McCarty M. Studies on the chemical nature of the substance inducing transformation of pneumococcal types: induction of transformation by a desoxyribonucleic acid fraction isolated from pneumococcus type III. J Exp Med. 1944;79:137–158.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  6. Saiki RK, Gelfand DH, Stoffel S, et al. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988;239(4839):487–491.

    Article  PubMed  CAS  Google Scholar 

  7. Hall JM, Lee MK, Newman B, et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science. 1990;250:1684–1690.

    Article  PubMed  CAS  Google Scholar 

  8. Solomon E, Ledbetter DH. Report of the Committee on the Genetic Constitution of Chromosome 17. Cytogenet Cell Genet. 1991;58:686–738.

    Article  Google Scholar 

  9. Schmutz J, Wheeler J, Grimwood J, et al. Quality assessment of the human genome sequence. Nature. 2004;429(6990):365–368.

    Article  PubMed  CAS  Google Scholar 

  10. Miki Y, Swensen J, Shattuck-Eidens D, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266(5182):66–71.

    Article  PubMed  CAS  Google Scholar 

  11. Wooster R, Neuhausen SL, Mangion J, et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science. 1994;265(5181):2088–2090.

    Article  PubMed  CAS  Google Scholar 

  12. Wooster R, Bignell G, Lancaster J, et al. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995;378:7897–7892.

    Article  Google Scholar 

  13. Tavtigian SV, Simard J, Rommens J, et al. The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat Genet. 1996;12:333–337.

    Article  PubMed  CAS  Google Scholar 

  14. Baker SG, Lichtenstein P, Kaprio J, Holm N. Genetic susceptibility to prostate, breast, and colorectal cancer among Nordic twins. Biometrics. 2005;61(1):55–63.

    Article  PubMed  Google Scholar 

  15. Locatelli I, Lichtenstein P, Yashin AI. The heritability of breast cancer: a Bayesian correlated frailty model applied to Swedish twins data. Twin Res. 2004;7(2):182–191.

    Article  PubMed  Google Scholar 

  16. Lichtenstein P, Holm NV, Verkasalo PK, et al. Environmental and heritable factors in the causation of cancer: analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med. 2000;343(2):78–85.

    Article  PubMed  CAS  Google Scholar 

  17. Risch N. The genetic epidemiology of cancer: interpreting family and twin studies and their implications for molecular genetic approaches. Cancer Epidemiol Biomarkers Prev. 2001;10(7):733–741.

    PubMed  CAS  Google Scholar 

  18. Claus EB, Risch N, Thompson WD. Autosomal dominant inheritance of early-onset breast cancer: implications for risk prediction. Cancer. 1994;73(3):643–651.

    Article  PubMed  CAS  Google Scholar 

  19. Gracia-Aznarez FJ, Fernandez V, Pita G, et al. Whole exome sequencing suggests much of non-BRCA1/BRCA2 familial breast cancer is due to moderate and low penetrance susceptibility alleles. PloS One. 2013;8(2):e55681.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Foulkes WD. Inherited susceptibility to common cancers. N Engl J Med. 2008;359(20):2143–2153.

    Article  PubMed  CAS  Google Scholar 

  21. Litim N, Labrie Y, Desjardins S, et al. Polymorphic variations in the FANCA gene in high-risk non-BRCA1/2 breast cancer individuals from the French Canadian population. Mole Oncol. 2013;7(1):85–100.

    Article  CAS  Google Scholar 

  22. Meindl A, Hellebrand H, Wiek C, et al. Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet. 2010;42(5):410–414.

    Article  PubMed  CAS  Google Scholar 

  23. Snape K, Eccles D, Evans C, et al. Germline RAD51C mutations confer susceptibility to ovarian cancer. Nat Genet. 2012;44(5):475–476.

    Article  PubMed  Google Scholar 

  24. Panchal S, Bordeleau L, Poll A, et al. Does family history predict the age at onset of new breast cancers in BRCA1 and BRCA2 mutation-positive families? Clin Genet. 2010;77(3):273–279.

    Article  PubMed  CAS  Google Scholar 

  25. Berry DA, Parmigiani G, Sanchez J, et al. Probability of carrying a mutation of breast-ovarian cancer gene BRCA1 based on family history. J Natl Cancer Inst. 1997;89:227–238.

    Article  PubMed  CAS  Google Scholar 

  26. Antoniou AC, Pharoah PD, McMullan G, et al. A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes. Br J Cancer. 2002;86(1):76–83.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  27. Tyrer J, Duffy SW, Cuzick J. A breast cancer prediction model incorporating familial and personal risk factors [published erratum appears in Stat Med. 2005;24(1):156]. Stat Med. 2004;23(7):1111–1130.

    Article  PubMed  Google Scholar 

  28. Mauer CB, Pirzadeh-Miller SM, Robinson LD, Euhus DM. The integration of next-generation sequencing panels in the clinical cancer genetics practice: an institutional experience. Genet Med. 2014;16(5):407–412.

    Article  PubMed  Google Scholar 

  29. Riley BD, Culver JO, Skrzynia C, et al. Essential elements of genetic cancer risk assessment, counseling, and testing: updated recommendations of the National Society of Genetic Counselors. J Genet Couns. 2012;21:151–161.

    Article  PubMed  Google Scholar 

  30. Cybulski C, Wokolorczyk D, Jakubowska A, et al. Risk of breast cancer in women with a CHEK2 mutation with and without a family history of breast cancer. J Clin Oncol. 2011;29(28):3747–3752.

    Article  PubMed  CAS  Google Scholar 

  31. Cybulski C, Gorski B, Huzarski T, et al. CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet. 2004;75(6):1131–1135.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. Byrd PJ, Srinivasan V, Last JI, et al. Severe reaction to radiotherapy for breast cancer as the presenting feature of ataxia telangiectasia. Br J Cancer. 2012;106(2):262–268.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  33. Tanteles GA, Murray RJ, Mills J, et al. Variation in telangiectasia predisposing genes is associated with overall radiation toxicity. Int J Radiat Oncol Biol Phys. 2012;84(4):1031–1036.

    Article  PubMed  CAS  Google Scholar 

  34. Pierce LJ, Haffty BG. Radiotherapy in the treatment of hereditary breast cancer. Semin Radiat Oncol. 2011;21(1):43–50.

    Article  PubMed  Google Scholar 

  35. National Comprehensive Cancer Network. Genetic/familial high-risk assessment: breast and ovarian. NCCN Clinical Practice Guidelines in Oncology v.1.2014. Vol 1. Fort Washington (PA): NCCN; 2014.

    Google Scholar 

  36. King MC, Marks JH, Mandell JB. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003;302:643–646.

    Article  PubMed  CAS  Google Scholar 

  37. Kotsopoulos J, Olopado OI, Ghadirian P, et al. Changes in body weight and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res. 2005;7(5):R833–843.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. Saslow D, Boetes C, Burke W, et al. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography [published erratum appears in CA Cancer J Clin. 2007;57(3):185]. CA Cancer J Clin. 2010;57(2):75–89.

    Article  Google Scholar 

  39. Gronwald J, Pijpe A, Byrski T, et al. Early radiation exposures and BRCA1-associated breast cancer in young women from Poland. Breast Cancer Res Treat. 2008;112(3):581–584.

    Article  PubMed  CAS  Google Scholar 

  40. Pijpe A, Andrieu N, Easton DF, et al. Exposure to diagnostic radiation and risk of breast cancer among carriers of BRCA1/2 mutations: retrospective cohort study (GENE-RAD-RISK). BMJ. 2012;345:e5660.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Berrington de Gonzalez A, Berg CD, Visvanathan K, Robson M. Estimated risk of radiation-induced breast cancer from mammographic screening for young BRCA mutation carriers. J Natl Cancer Inst. 2009;101(3):205–209.

    Article  Google Scholar 

  42. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90(18):1371–1388.

    Article  PubMed  CAS  Google Scholar 

  43. Vogel VG, Costantino JP, Wickerham DL, et al. Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: preventing breast cancer. Cancer Prev Res (Phila). 2010;3(6):696–706.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  44. Goss PE, Ingle JN, Ales-Martinez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med. 2011;364(25):2381–2391.

    Article  PubMed  CAS  Google Scholar 

  45. Cuzick J, Sestak I, Forbes JF, et al. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet. 2014;383(9922):1041–1048.

    Article  PubMed  CAS  Google Scholar 

  46. Phillips KA, Milne RL, Rookus MA, et al. Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. J Clin Oncol. 2013;31(25):3091–3099.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  47. Gronwald J, Tung N, Foulkes WD, et al. Tamoxifen and contralateral breast cancer in BRCA1 and BRCA2 carriers: an update. Int J Cancer. 2006;118(9):2281–2284.

    Article  PubMed  CAS  Google Scholar 

  48. Domchek SM, Friebel TM, Singer CF, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA. 2010;304(9):967–975.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  49. Kauff ND, Domchek SM, Friebel TM, et al. Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study. J Clin Oncol. 2008;26(8):1331–1337.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Finch AP, Lubinski J, Moller P, et al. Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J Clin Oncol. 2014;32(15):1547–53.

    Article  PubMed  Google Scholar 

  51. Sitzmann JV, Wiebke EA. Risk-reducing appendectomy and the elimination of BRCA1-associated intraperitoneal cancer. JAMA Surg. 2013;148(3):285–291; discussion 291.

    Article  PubMed  Google Scholar 

  52. Heemskerk-Gerritsen BA, Brekelmans CT, Menke-Pluymers MB, et al. Prophylactic mastectomy in BRCA1/2 mutation carriers and women at risk of hereditary breast cancer: long-term experiences at the Rotterdam Family Cancer Clinic. Ann Surg Oncol. 2007;14(12):3335–3344.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Meijers-Heijboer H, van Geel B, van Putten WL, et al. Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med. 2001;345(3):159–164.

    Article  PubMed  CAS  Google Scholar 

  54. Hartmann LC, Schaid DJ, Woods JE, et al. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med. 1999;340(2):77–84.

    Article  PubMed  CAS  Google Scholar 

  55. Rusby JE, Smith BL, Gui GP. Nipple-sparing mastectomy. Br J Surg. 2010;97(3):305–316.

    Article  PubMed  CAS  Google Scholar 

  56. Liebens FP, Carly B, Pastijn A, Rozenberg S. Management of BRCA1/2 associated breast cancer: a systematic qualitative review of the state of knowledge in 2006. Eur J Cancer. 2007;43(2):238–257.

    Article  PubMed  CAS  Google Scholar 

  57. Pierce LJ, Phillips KA, Griffith KA, et al. Local therapy in BRCA1 and BRCA2 mutation carriers with operable breast cancer: comparison of breast conservation and mastectomy. Breast Cancer Res Treat. 2010;121(2):389–398.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Evans DG, Ingham SL, Baildam A, et al. Contralateral mastectomy improves survival in women with BRCA1/2-associated breast cancer. Breast Cancer Res Treat. 2013;140(1):135–142.

    Article  PubMed  CAS  Google Scholar 

  59. Metcalfe K, Gershman S, Ghadirian P, et al. Contralateral mastectomy and survival after breast cancer in carriers of BRCA1 and BRCA2 mutations: retrospective analysis. BMJ. 2014;348:g226.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Wysocki PJ, Korski K, Lamperska K, Zaluski J, Mackiewicz A. Primary resistance to docetaxel-based chemotherapy in metastatic breast cancer patients correlates with a high frequency of BRCA1 mutations. Med Sci Monit. 2008;14(7):SC7-10.

    PubMed  CAS  Google Scholar 

  61. Byrski T, Gronwald J, Huzarski T, et al. Response to neo-adjuvant chemotherapy in women with BRCA1-positive breast cancers. Breast Cancer Res Treat. 2008;108(2):289–296.

    Article  PubMed  CAS  Google Scholar 

  62. Stordal B, Pavlakis N, Davey R. A systematic review of platinum and taxane resistance from bench to clinic: an inverse relationship. Cancer Treat Rev. 2007;33:688–703.

    Article  PubMed  CAS  Google Scholar 

  63. Fedier A, Steiner RA, Schwarz VA, Lenherr L, Haller Z, Fink D. The effect of loss of BRCA1 on the sensitivity to anticancer agents in p53-deficient cells. Int J Oncol. 2003;22:1169–1173.

    PubMed  CAS  Google Scholar 

  64. Byrski T, Gronwald J, Huzarski T, et al. Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy. J Clin Oncol. 2010;28(3):375–379.

    Article  PubMed  CAS  Google Scholar 

  65. Byrski T, Huzarski T, Dent R, et al. Response to neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients. Breast Cancer Res Treat. 2009;115(2):359–363.

    Article  PubMed  CAS  Google Scholar 

  66. Pennington KP, Walsh T, Harrell MI, et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res. 2014;20(3):764–775.

    Article  PubMed  CAS  Google Scholar 

  67. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361(2):123–134.

    Article  PubMed  CAS  Google Scholar 

  68. Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet. 2010;376(9737):235–244.

    Article  PubMed  CAS  Google Scholar 

  69. Min A, Im SA, Yoon YK, et al. RAD51C-deficient cancer cells are highly sensitive to the PARP inhibitor olaparib. Mol Cancer Ther. 2013;12(6):865–877.

    Article  PubMed  CAS  Google Scholar 

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  1. Johns Hopkins Hospital, Baltimore, MD, USA

    David Euhus MD

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  1. David Euhus MD
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Correspondence to David Euhus MD.

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Euhus, D. Genetic Testing Today. Ann Surg Oncol 21, 3209–3215 (2014). https://doi.org/10.1245/s10434-014-3906-0

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