Skip to main content

Advertisement

SpringerLink
Log in

Evaluation of BRCA1 mutations in an unselected patient population with triple-negative breast cancer

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Triple-negative breast cancer (TNBC) is characterized by aggressive behavior and poor prognosis. While >50 % of patients with inherited BRCA1 mutations have TNBC, the prevalence of BRCA1 mutations in patients with TNBC remains unclear. Deciphering the relationship between BRCA1 and TNBC is critical to understanding the etiology of TNBC, leading to improved patient counseling and treatment. All female patients with TNBC enrolled in the Clinical Breast Care Project were identified. Genomic DNA was isolated from blood and the exonic regions of the BRCA1 gene were amplified and sequenced. Sequence data was analyzed and mutations identified using Sequencher 4.10.1. Of the 190 women with TNBC, genomic DNA was available for 182. Seventy percent of patients were considered high-risk for having a BRCA1 mutation based on the National Comprehensive Cancer Network criteria. Clinically relevant mutations were detected in 16 (9 %) patients ranging in age from 26 to 69 years at diagnosis. Six of these patients were diagnosed >50 years. The C61G mutation was found in three Caucasian women diagnosed >40 years, while six African-American women had mutations, including the 943ins10 West African founder mutation. Upon conclusion, causative BRCA1 mutations were detected in 9 % of TNBC patients, including patients without significant family histories and/or diagnosed at a later age. The mutation frequency in patients <60 years was 11.2–18.3 % in those patients with significant risk factors and 4.6 % in those without, while in patients >60 years, the mutation frequency was 3.5–7.7 % in patients with risk factors, 2.3 % in those without. Thus, evaluation of additional risk factors in both patients younger and older than 60 years should improve the identification of TNBC patients benefiting from genetic testing of BRCA1.

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

Abbreviations

BRCA1:

Breast cancer 1 gene

CBCP:

Clinical Breast Care Project

ER:

Estrogen receptor

HER2:

V-ERB-B2 erythroblastic leukemia viral oncogene homolog 2

PARP:

Poly(ADP-ribose) polymerase

PCR:

Polymerase chain reaction

PR:

Progesterone receptor

TNBC:

Triple-negative breast cancer

References

  1. Rakha EA, Ellis IO (2009) Triple-negative/basal-like breast cancer: review. Pathology 41(1):40–47

    Article  PubMed  Google Scholar 

  2. Pal SK, Childs BH, Pegram M (2011) Triple negative breast cancer: unmet medical needs. Breast Cancer Res Treat 125(3):627–636

    Article  PubMed  CAS  Google Scholar 

  3. Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, Lickley LA, Rawlinson E, Sun P, Narod SA (2007) Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 13(15 Pt 1):4429–4434

    Article  PubMed  Google Scholar 

  4. Lin NU, Claus E, Sohl J, Razzak AR, Amaout A, Winer EP (2008) Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases. Cancer 113(10):2638–2645

    Article  PubMed  Google Scholar 

  5. Anders C, Carey LA (2008) Understanding and treating triple-negative breast cancer. Oncology (Williston Park) 22(11):1233–1243

    Google Scholar 

  6. Atchley DP, Albarracin CT, Lopez A, Valero V, Amos CI, Gonzalez-Angulo AM, Hortobagyi GN, Arun BK (2006) Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol 26(26):4282–4288

    Article  Google Scholar 

  7. Diaz LK, Cryns VL, Symmans F, Sneige N (2007) Triple negative breast carcinoma and the basal phenotype: from expression profiling to clinical practice. Adv Anat Pathol 14(6):419–430

    Article  PubMed  CAS  Google Scholar 

  8. Liu S, Ginestier C, Charafe-Jauffret E, Foco H, Kleer CG, Merajver SD, Dontu G, Wicha MS (2008) BRCA1 regulates human mammary stem/progenitor cell fate. Proc Natl Acad Sci USA 105(5):1680–1685

    Article  PubMed  CAS  Google Scholar 

  9. Silver DP (2011) PARP inhibition in triple negative breast cancer, November 8, 11

  10. American Joint Committee on Cancer (2010) AJCC cancer staging manual, 7th edn. Springer, New York

    Google Scholar 

  11. Bloom HJ, Richardson WW (1957) Histological grading and prognosis in breast cancer. Br J Cancer 11:359–377

    Article  PubMed  CAS  Google Scholar 

  12. Elston CW, Ellis IO (1991) Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow up. Histopathology 19:403–410

    Article  PubMed  CAS  Google Scholar 

  13. Hammond MEH, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL et al (2010) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 28(16):2784–2795

    Article  PubMed  Google Scholar 

  14. National Comprehensive Cancer Network (2012) Genetic/familial high-risk assessment: breast and ovarian cancer. 1.2012

  15. Hecker KH, Roux KH (1996) High and low annealing temperatures increase both specificity and yield in touchdown and step-down PCR. Biotechniques 20:478–485

    PubMed  CAS  Google Scholar 

  16. Bayraktar S, Gutierrez-Barrera AM, Liu D, Tasbas T, Akar U, Litton JK, Lin E, Albarracin CT, Meric-Bernstam F, Gonzalez-Angulo AM, Hortobagyi GN, Arun BK (2011) Outcome of triple-negative breast cancer in patients with or without deleterious BRCA mutations. Breast Cancer Res Treat 130:145–153

    Article  PubMed  CAS  Google Scholar 

  17. Tischkowitz MD, Foulkes WD (2006) The basal phenotype of BRCA1-related breast cancer: past, present and future. Cell Cycle 5(9):963–967

    Article  PubMed  CAS  Google Scholar 

  18. Lidereau R, Eisinger F, Champeme M-H, Nogues C, Bieche I, Birnbaum D, Pallud C, Jacquemier J, Sobol H (2000) Major improvement in the efficacy of BRCA1 mutation screening using morphoclinical features of breast cancer. Cancer Res 60:1206–1210

    PubMed  CAS  Google Scholar 

  19. Chang J, Hilsenbeck SG, Sng JH, Wong J, Ragu GC (2001) Pathological features and BRCA1 mutation screening in premenopausal breast cancer patients. Clin Cancer Res 7:1739–1742

    PubMed  CAS  Google Scholar 

  20. Foulkes WD, Stafansson IM, Chappuis PO, Begin LR, Goffin JR, Wong N, Trudel M, Akslen LA (2003) Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst 95(19):1482–1485

    Article  PubMed  CAS  Google Scholar 

  21. Sorlie T, Tibshirania R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S, Demeter J, Perou CM, Lonning PE, Brown PO, Borresen-Dale AL, Botstein D (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 100(14):8418–8423

    Article  PubMed  CAS  Google Scholar 

  22. Young SR, Pilarski RT, Donenberg T, Shapiro C, Hammon LS, Miller J, Brooks KA, Cohen S, Tenenholz B, DeSai D, Zandvakili I, Royer R, Li S, Narod SR (2009) The prevalence of BRCA1 mutations among young women with triple-negative breast cancer. BMC Cancer 9:86

    Article  PubMed  CAS  Google Scholar 

  23. Evans DG, Howell A, Ward D, Lalloo F, Jones JL, Eccles DM (2011) Prevalence of BRCA1 and BRCA2 mutations in triple negative breast cancer. J Med Genet 48:520–522

    Article  PubMed  CAS  Google Scholar 

  24. Gonzalez-Angulo AM, Timms KM, Liu S, Chen H, Litton JK, Potter J, Lanchbury JS, Stemke-Hale K, Hennessy BT, Arun BK, Hortobagyi GN, Do K-A, Mills GB, Meric-Bernstam F (2011) Incidence and outcome of BRCA mutations in unselected patients with triple receptor-negative breast cancer. Clin Cancer Res 17(5):1082–1089

    Article  PubMed  CAS  Google Scholar 

  25. Hartman A-R, Kaldate RR, Sailer LM, Painter L, Crier CE, Endsley RR, Griffin M, Hamilton SA, Frye CA, Silberman MA, Wenstrup RJ, Sandbach JF (2012) Prevalence of BRCA mutations in an unselected population of triple-negative breast cancer. Cancer 118(11):2787–2795

    Article  PubMed  CAS  Google Scholar 

  26. Malone KE, Daling JR, Doody DR, Hsu L, Bernstein L, Coates RJ, Marchbanks PA, Simon MS, McDonald JA, Norman SA, Strom BL, Burkman RT, Urslin G, Deapen D, Weiss LK, Folger S, Madeoy JJ, Friedrichsen DM, Suter NM, Humphrey MC, Spirtas R, Ostrander EA (2006) Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35–64 years. Cancer Res 66(16):8297–8308

    Article  PubMed  CAS  Google Scholar 

  27. Mazoyer S (2005) Genomic rearrangements in the BRCA1 and BRCA2 genes. Hum Mutat 25:415–422

    Article  PubMed  CAS  Google Scholar 

  28. Mefford HC, Baumbach L, Panguluri RC, Whitfield-Broome C, Szabo C, Smith S, King MC, Dunston G, Stoppa-Lyonnet D, Arena F (1999) Evidence for a BRCA1 founder mutation in families of West African ancestry. Am J Hum Genet 65(2):575–578

    Article  PubMed  CAS  Google Scholar 

  29. Fackenthal JD, Zhang J, Zhang B, Zheng Y, Hagos F, Burrill DR, Niu Q, Huo D, Sveen WE, Ogundiran T, Adebamowo C, Odetunde A, Falusi AG, Olopade OI (2012) High prevalence of BRCA1 and BRCA2 mutations in unselected Nigerian breast cancer patients. Int J Cancer 131(5):1114–1123

    Article  PubMed  CAS  Google Scholar 

  30. Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, Karaca G, Troester MA, Tse CK, Edminston S, Deming SL, Geradts J, Cheang MCU, Nielson TO, Moorman PG, Earp HS, Milikan RC (2006) Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 295(21):2492–2502

    Article  PubMed  CAS  Google Scholar 

  31. Zhang J, Fackenthal JD, Zheng Y, Huo D, Hou N, Niu Q, Zvosec C, Ogundiran TO, Hennis AJ, Leske MC, Nemesure B, Wu S-Y, Olopade OI (2012) Recurrent BRCA1 and BRCA2 mutations in breast cancer patients of African ancestry. Breast Cancer Res Treat 134(2):889–894

    Article  PubMed  CAS  Google Scholar 

  32. Kwon JS, Gutierrez-Barrera AM, Young D, Sun CC, Daniels MS, Lu KH, Arun B (2010) Expanding the criteria for BRCA mutation testing in breast cancer survivors. J Clin Oncol 28(27):4214–4220

    Article  PubMed  Google Scholar 

  33. Ashworth A (2008) A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J Clin Oncol 26:3785–3790

    Article  PubMed  CAS  Google Scholar 

  34. Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, O’Connor MJ, Ashworth A, Carmichael J, Kaye SB, Schellens JH, de Bono JS (2009) Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361(2):123–134

    Article  PubMed  CAS  Google Scholar 

  35. O’Shaughnessy J, Osborne C, Pippen JE, Yoffe M, Patt D, Rocha C, Koo IC, Sherman BM, Bradley C (2011) Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med 364(3):205–214

    Article  PubMed  Google Scholar 

  36. Tutt A, Robson M, Garber JE, Domcheck SM, Audeh MW, Weitzel JN, Friedlander M, Arun B, Loman N, Schmutzler RK, Wardley A, Mitchell G, Earl H, Wickens M, Carmichael J (2010) Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 376(9737):235–244

    Article  PubMed  CAS  Google Scholar 

  37. Gelmon KA, Tischkowitz M, Mackay H, Swenerton K, Robidoux A, Tonkin K, Hirte H, Huntsman D, Clemons M, Gilks B, Yerushalmi R, Macpherson E, Carmichael J, Oza A (2011) Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 12(9):852–861

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Allyson Valente for her critical review of this manuscript. This research was supported by a grant from the United States Department of Defense (Military Molecular Medicine Initiative MDA W81XWH-05-2-0075, Protocol 01-20006). The opinion and assertions contained herein are the private views of the authors and are not to be construed as official or as representing the views of the Department of the Army or the Department of Defense.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

The experiments performed here comply with the current laws of the United States.

Author information

Authors and Affiliations

  1. Windber Research Institute, 620 Seventh Street, Windber, PA, 15963, USA

    Seth Rummel & Erika Varner

  2. Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20852, USA

    Craig D. Shriver

  3. Clinical Breast Care Project, Henry M. Jackson Foundation for the Advancement of Military Medicine, 620 Seventh Street, Windber, PA, 15963, USA

    Rachel E. Ellsworth

Authors
  1. Seth Rummel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Erika Varner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Craig D. Shriver
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rachel E. Ellsworth
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rachel E. Ellsworth.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rummel, S., Varner, E., Shriver, C.D. et al. Evaluation of BRCA1 mutations in an unselected patient population with triple-negative breast cancer. Breast Cancer Res Treat 137, 119–125 (2013). https://doi.org/10.1007/s10549-012-2348-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-012-2348-2

Keywords

Search

Navigation