Skip to main content

Advertisement

SpringerLink
Log in

The Changing Landscape of Genetic Testing for Inherited Breast Cancer Predisposition

  • Breast Cancer (ML Telli, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

The advent of multiple-gene germline panel testing has led to significant advances in hereditary breast and ovarian cancer risk assessment. These include guideline-specific cancer risk management recommendations for patients and their families, such as screening with breast magnetic resonance imaging and risk-reducing surgeries, which have the potential to reduce substantially the morbidity and mortality associated with a hereditary cancer predisposition. However, controversy remains about the clinical validity and actionability of genetic testing in a broader patient population. We discuss events leading to the wider availability of commercialized multiple-gene germline panel testing, the recent data that support using this powerful tool to improve cancer risk assessment and reduction strategies, and remaining challenges to clinical optimization of this new genetic technology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Offit K, Bradbury A, Storm C, et al. Gene patents and personalized cancer care: impact of the myriad case on clinical oncology. J Clin Oncol. 2013;31:2743–8.

    Article  PubMed  Google Scholar 

  2. Couch FJ, Nathanson KL, Offit K. Two decades after BRCA: setting paradigms in personalized cancer care and prevention. Science. 2014;343:1466–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 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 

  4. Wooster R, Neuhausen SL, Mangion J, et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science. 1994;265:2088–90.

    Article  CAS  PubMed  Google Scholar 

  5. Li X, Heyer WD. Homologous recombination in DNA repair and DNA damage tolerance. Cell Res. 2008;18:99–113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ford D, Easton DF, Stratton M, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The breast cancer linkage consortium. Am J Hum Genet. 1998;62:676–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. King MC, Marks JH, Mandell JB, et al. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003;302:643–6.

    Article  CAS  PubMed  Google Scholar 

  8. Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72:1117–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol. 2007;25:1329–33.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Kurian AW, Kingham KE, Ford JM. Next-generation sequencing for hereditary breast and gynecologic cancer risk assessment. Curr Opin Obstet Gynecol. 2015;27:23–33.

    Article  PubMed  Google Scholar 

  11. 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;304:967–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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;32:1547–53.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Daly MB, Pilarski R, Berry M, et al. NCCN guidelines insights: genetic/familial high-risk assessment: breast and ovarian, version 2.2017. J Natl Compr Cancer Netw. 2017;15:9–20.

    Article  Google Scholar 

  14. Kesselheim AS, Mello MM. Gene patenting—is the pendulum swinging back? N Engl J Med. 2010;362:1855–8.

    Article  CAS  PubMed  Google Scholar 

  15. Shendure J, Ji H. Next-generation DNA sequencing. Nat Biotechnol. 2008;26:1135–45.

    Article  CAS  PubMed  Google Scholar 

  16. Dewey FE, Grove ME, Pan C, et al. Clinical interpretation and implications of whole-genome sequencing. JAMA. 2014;311:1035–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mainiero MB, Lourenco A, Mahoney MC, et al. ACR appropriateness criteria breast cancer screening. J Am Coll Radiol. 2013;10:11–4.

    Article  PubMed  Google Scholar 

  18. Saslow D, Boetes C, Burke W, et al. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin. 2007;57:75–89.

    Article  PubMed  Google Scholar 

  19. Kurian AW, Ford JM. Multigene panel testing in oncology practice: how should we respond? JAMA Oncol. 2015;1:277–8.

    Article  PubMed  Google Scholar 

  20. Graffeo R, Livraghi L, Pagani O, et al. Time to incorporate germline multigene panel testing into breast and ovarian cancer patient care. Breast Cancer Res Treat. 2016;160:393–410.

    Article  CAS  PubMed  Google Scholar 

  21. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 2014;15:852–61.

    Article  CAS  PubMed  Google Scholar 

  22. Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol. 2017;18:75–87.

    Article  CAS  PubMed  Google Scholar 

  23. Churpek JE, Walsh T, Zheng Y, et al. Inherited predisposition to breast cancer among African American women. Breast Cancer Res Treat. 2015;149:31–9.

    Article  CAS  PubMed  Google Scholar 

  24. • Couch FJ, Hart SN, Sharma P, et al Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast nancer. Journal of Clinical Oncology 2015;33. Characterized predisposition genes associated at higher frequency in triple-negative breast cancer beyond BRCA1/2.

  25. Castera L, Krieger S, Rousselin A, et al Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes. Eur J Hum Genet 2014.

  26. Kurian AW, Hare EE, Mills MA, et al. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol. 2014;32:2001–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Tung N, Battelli C, Allen B, et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015;121:25–33.

    Article  CAS  PubMed  Google Scholar 

  28. • Desmond A, Kurian AW, Gabree M, et al. Clinical actionability of multigene panel testing for hereditary breast and ovarian cancer risk assessment. JAMA Oncol. 2015;1:943–51. Assessed the potential clinical effect of multigene testing by determining the clinical actionability of such test results for individuals harboring deleterious gene mutations.

    Article  PubMed  Google Scholar 

  29. Tung N, Lin NU, Kidd J, et al. Frequency of germline mutations in 25 cancer susceptibility genes in a sequential series of patients with breast cancer. J Clin Oncol. 2016;34:1460–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Idos G, Kurian AW, Ricker CN, et al. Yield of multiplex panel testing compared to expert opinion and validated prediction models. Chicago: Presented at the American Society of Oncology Annual Meeting; 2016.

    Google Scholar 

  31. Thompson ER, Rowley SM, Li N, et al. Panel testing for familial breast cancer: calibrating the tension between research and clinical care. J Clin Oncol. 2016;34:1455–9.

    Article  CAS  PubMed  Google Scholar 

  32. Hall MJ, Reid JE, Burbidge LA, et al. BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer. Cancer. 2009;115:2222–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. LaDuca H, Stuenkel AJ, Dolinsky JS, et al. Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients. Genet Med. 2014;16:830–7.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Selkirk CG, Vogel KJ, Newlin AC, et al. Cancer genetic testing panels for inherited cancer susceptibility: the clinical experience of a large adult genetics practice. Familial Cancer. 2014;13:527–36.

    Article  CAS  PubMed  Google Scholar 

  35. Kurian AW, Antoniou AC, Domchek SM. Refining breast cancer risk stratification: additional genes, additional information. Am Soc Clin Oncol Educ Book. 2016;35:44–56.

    Article  PubMed  Google Scholar 

  36. • Balmana J, Digiovanni L, Gaddam P, et al. Conflicting interpretation of genetic variants and cancer risk by commercial laboratories as assessed by the prospective registry of multiplex testing. J Clin Oncol. 2016;34:4071–8. Assessed the discrepancies in variants of uncertain significance between genetic testing laboratories. Results show that a substantial number of conflicting interpretations exist between laboratories, and these may have clinical implications for patients.

    Article  PubMed  Google Scholar 

  37. Renwick A, Thompson D, Seal S, et al. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet. 2006;38:873–5.

    Article  CAS  PubMed  Google Scholar 

  38. Mavaddat N, Peock S, Frost D, et al. Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE. J Natl Cancer Inst. 2013;105:812–22.

    Article  CAS  PubMed  Google Scholar 

  39. Kaurah P, MacMillan A, Boyd N, et al. Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA. 2007;297:2360–72.

    Article  CAS  PubMed  Google Scholar 

  40. Pharoah PD, Guilford P, Caldas C, et al. Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology. 2001;121:1348–53.

    Article  CAS  PubMed  Google Scholar 

  41. van der Post RS, Vogelaar IP, Carneiro F, et al. Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers. J Med Genet. 2015;52:361–74.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Meijers-Heijboer H, van den Ouweland A, Klijn J, et al. Low-penetrance susceptibility to breast cancer due to CHEK2* 1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet. 2002;31:55–9.

    Article  CAS  PubMed  Google Scholar 

  43. Weischer M, Bojesen SE, Ellervik C, et al. CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls. J Clin Oncol. 2008;26:542–8.

    Article  PubMed  Google Scholar 

  44. Bartkova J, Tommiska J, Oplustilova L, et al. Aberrations of the MRE11-RAD50-NBS1 DNA damage sensor complex in human breast cancer: MRE11 as a candidate familial cancer-predisposing gene. Mol Oncol. 2008;2:296–316.

    Article  PubMed  Google Scholar 

  45. Zhang G, Zeng Y, Liu Z, et al. Significant association between Nijmegen breakage syndrome 1 657del5 polymorphism and breast cancer risk. Tumour Biol. 2013;34:2753–7.

    Article  CAS  PubMed  Google Scholar 

  46. Seminog OO, Goldacre MJ. Age-specific risk of breast cancer in women with neurofibromatosis type 1. Br J Cancer. 2015;112:1546–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Antoniou AC, Casadei S, Heikkinen T, et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med. 2014;371:497–506.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Tan MH, Mester JL, Ngeow J, et al. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res. 2012;18:400–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Pilarski R, Eng C. Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome. J Med Genet. 2004;41:323–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hearle N, Schumacher V, Menko FH, et al. Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin Cancer Res. 2006;12:3209–15.

    Article  CAS  PubMed  Google Scholar 

  51. Gonzalez KD, Noltner KA, Buzin CH, et al. Beyond Li Fraumeni syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol. 2009;27:1250–6.

    Article  CAS  PubMed  Google Scholar 

  52. Castera L, Krieger S, Rousselin A, et al. Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes. Eur J Hum Genet. 2014;22:1305–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Comprehensive molecular portraits of human breast tumours. Nature 2012;490:61–70.

Download references

Author information

Authors and Affiliations

  1. Division of Oncology, University of Colorado, 1665 Aurora Ct, Mailstop F704, Aurora, CO, 80045, USA

    Anosheh Afghahi MD, MPH

  2. Stanford University, HRP Redwood Building, Room T254A 259 Campus Drive, Stanford, CA, 94305-5405, USA

    Allison W. Kurian MD, MSc

Authors
  1. Anosheh Afghahi MD, MPH
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Allison W. Kurian MD, MSc
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anosheh Afghahi MD, MPH.

Ethics declarations

Conflict of Interest

Anosheh Afghahi declares that she has no conflict of interest.

Allison W. Kurian has received research support through grants from Myriad Genetics, Ambry Genetics, and Invitae.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Breast Cancer

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Afghahi, A., Kurian, A.W. The Changing Landscape of Genetic Testing for Inherited Breast Cancer Predisposition. Curr. Treat. Options in Oncol. 18, 27 (2017). https://doi.org/10.1007/s11864-017-0468-y

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11864-017-0468-y

Keywords

Search

Navigation