Advertisement

Hormones and Cancer

, Volume 9, Issue 4, pp 215–228 | Cite as

The Impact of ESR1 Mutations on the Treatment of Metastatic Breast Cancer

  • Sasha M. Pejerrey
  • Derek Dustin
  • Jin-Ah Kim
  • Guowei Gu
  • Yassine Rechoum
  • Suzanne A. W. FuquaEmail author
Review

Abstract

After nearly 20 years of research, it is now established that mutations within the estrogen receptor (ER) gene, ESR1, frequently occur in metastatic breast cancer and influence response to hormone therapy. Though early studies presented differing results, sensitive sequencing techniques now show that ESR1 mutations occur at a frequency between 20 and 40% depending on the assay method. Recent studies have focused on several “hot spot mutations,” a cluster of mutations found in the hormone-binding domain of the ESR1 gene. Throughout the course of treatment, tumor evolution can occur, and ESR1 mutations emerge and become enriched in the metastatic setting. Sensitive techniques to continually monitor mutant burden in vivo are needed to effectively treat patients with mutant ESR1. The full impact of these mutations on tumor response to different therapies remains to be determined. However, recent studies indicate that mutant-bearing tumors may be less responsive to specific hormonal therapies, and suggest that aromatase inhibitor (AI) therapy may select for the emergence of ESR1 mutations. Additionally, different mutations may respond discretely to targeted therapies. The need for more preclinical mechanistic studies on ESR1 mutations and the development of better agents to target these mutations are urgently needed. In the future, sequential monitoring of ESR1 mutational status will likely direct personalized therapeutic regimens appropriate to each tumor’s unique mutational landscape.

Notes

Funding Information

The study received funding from the National Institutes of Health NCI RO1 CA207270, Breast Cancer Research Foundation 16-056, National Institutes of Health NCI R01CA072038, and Cancer Prevention Research Institute of Texas RP150440.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Hull DF 3rd, Clark GM, Osborne CK, Chamness GC, Knight WA 3rd, McGuire WL (1983) Multiple estrogen receptor assays in human breast cancer. Cancer Res 43(1):413–416PubMedGoogle Scholar
  2. 2.
    Gutierrez MC, Detre S, Johnston S, Mohsin SK, Shou J, Allred DC, Schiff R, Osborne CK, Dowsett M (2005) Molecular changes in tamoxifen-resistant breast cancer: relationship between estrogen receptor, HER-2, and p38 mitogen-activated protein kinase. J Clin Oncol 23(11):2469–2476CrossRefPubMedGoogle Scholar
  3. 3.
    Herman ME, Katzenellenbogen BS (1996) Response-specific antiestrogen resistance in a newly characterized MCF-7 human breast cancer cell line resulting from long-term exposure to trans-hydroxytamoxifen. J Steroid Biochem Mol Biol 59(2):121–134CrossRefPubMedGoogle Scholar
  4. 4.
    Gluck S (2014) Extending the clinical benefit of endocrine therapy for women with hormone receptor-positive metastatic breast cancer: differentiating mechanisms of action. Clin Breast Cancer 14(2):75–84CrossRefPubMedGoogle Scholar
  5. 5.
    Cardoso F, Costa A, Norton L, Senkus E, Aapro M, Andre F, Barrios CH, Bergh J, Biganzoli L, Blackwell KL et al (2014) ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2). Breast 23(5):489–502CrossRefPubMedGoogle Scholar
  6. 6.
    Cardoso F, Costa A, Norton L, Senkus E, Aapro M, Andre F, Barrios CH, Bergh J, Biganzoli L, Blackwell KL et al (2014) ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2)dagger. Ann Oncol 25(10):1871–1888CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Fuqua SA (2001) The role of estrogen receptors in breast cancer metastasis. J Mammary Gland Biol Neoplasia 6(4):407–417CrossRefPubMedGoogle Scholar
  8. 8.
    Giguere V (2014) Estrogen receptor mutations in breast cancer—an anticipated “rediscovery?”. Mol Endocrinol 28(4):427–428CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Gottardis MM, Robinson SP, Jordan VC (1988) Estradiol-stimulated growth of MCF-7 tumors implanted in athymic mice: a model to study the tumoristatic action of tamoxifen. J Steroid Biochem 30(1–6):311–314CrossRefPubMedGoogle Scholar
  10. 10.
    Gottardis MM, Jordan VC (1988) Development of tamoxifen-stimulated growth of MCF-7 tumors in athymic mice after long-term antiestrogen administration. Cancer Res 48(18):5183–5187PubMedGoogle Scholar
  11. 11.
    Wolf DM, Jordan VC (1994) The estrogen receptor from a tamoxifen stimulated MCF-7 tumor variant contains a point mutation in the ligand binding domain. Breast Cancer Res Treat 31(1):129–138CrossRefPubMedGoogle Scholar
  12. 12.
    Levenson AS, MacGregor Schafer JI, Bentrem DJ, Pease KM, Jordan VC (2001) Control of the estrogen-like actions of the tamoxifen-estrogen receptor complex by the surface amino acid at position 351. J Steroid Biochem Mol Biol 76(1–5):61–70CrossRefPubMedGoogle Scholar
  13. 13.
    Knowlden JM, Hutcheson IR, Barrow D, Gee JM, Nicholson RI (2005) Insulin-like growth factor-I receptor signaling in tamoxifen-resistant breast cancer: a supporting role to the epidermal growth factor receptor. Endocrinology 146(11):4609–4618CrossRefPubMedGoogle Scholar
  14. 14.
    Knowlden JM, Hutcheson IR, Jones HE, Madden T, Gee JM, Harper ME, Barrow D, Wakeling AE, Nicholson RI (2003) Elevated levels of epidermal growth factor receptor/c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 cells. Endocrinology 144(3):1032–1044CrossRefPubMedGoogle Scholar
  15. 15.
    Fan M, Yan PS, Hartman-Frey C, Chen L, Paik H, Oyer SL, Salisbury JD, Cheng AS, Li L, Abbosh PH et al (2006) Diverse gene expression and DNA methylation profiles correlate with differential adaptation of breast cancer cells to the antiestrogens tamoxifen and fulvestrant. Cancer Res 66(24):11954–11966CrossRefPubMedGoogle Scholar
  16. 16.
    Shaw LE, Sadler AJ, Pugazhendhi D, Darbre PD (2006) Changes in oestrogen receptor-alpha and -beta during progression to acquired resistance to tamoxifen and fulvestrant (Faslodex, ICI 182,780) in MCF7 human breast cancer cells. J Steroid Biochem Mol Biol 99(1):19–32CrossRefPubMedGoogle Scholar
  17. 17.
    Santen RJ, Song RX, Zhang Z, Kumar R, Jeng MH, Masamura S, Lawrence J Jr, MacMahon LP, Yue W, Berstein L (2005) Adaptive hypersensitivity to estrogen: mechanisms and clinical relevance to aromatase inhibitor therapy in breast cancer treatment. J Steroid Biochem Mol Biol 95(1–5):155–165CrossRefPubMedGoogle Scholar
  18. 18.
    Chen S, Masri S, Hong Y, Wang X, Phung S, Yuan YC, Wu X (2007) New experimental models for aromatase inhibitor resistance. J Steroid Biochem Mol Biol 106(1–5):8–15CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Brodie A, Jelovac D, Macedo L, Sabnis G, Tilghman S, Goloubeva O (2005) Therapeutic observations in MCF-7 aromatase xenografts. Clin Cancer Res 11(2 Pt 2):884s–888sPubMedGoogle Scholar
  20. 20.
    Jelovac D, Macedo L, Handratta V, Long BJ, Goloubeva OG, Ingle JN, Brodie AM (2004) Effects of exemestane and tamoxifen in a postmenopausal breast cancer model. Clin Cancer Res 10(21):7375–7381CrossRefPubMedGoogle Scholar
  21. 21.
    Santen RJ, Song RX, Zhang Z, Kumar R, Jeng MH, Masamura A, Lawrence J Jr, Berstein L, Yue W (2005) Long-term estradiol deprivation in breast cancer cells up-regulates growth factor signaling and enhances estrogen sensitivity. Endocr Relat Cancer 12(Suppl 1):S61–S73CrossRefPubMedGoogle Scholar
  22. 22.
    Johnston SR, Martin LA, Head J, Smith I, Dowsett M (2005) Aromatase inhibitors: combinations with fulvestrant or signal transduction inhibitors as a strategy to overcome endocrine resistance. J Steroid Biochem Mol Biol 95(1–5):173–181CrossRefPubMedGoogle Scholar
  23. 23.
    Piccart M, Hortobagyi GN, Campone M, Pritchard KI, Lebrun F, Ito Y, Noguchi S, Perez A, Rugo HS, Deleu I et al (2014) Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2dagger. Ann Oncol 25(12):2357–2362CrossRefPubMedGoogle Scholar
  24. 24.
    Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, Abadie-Lacourtoisie S, Eymard JC, Debled M, Spaeth D et al (2012) Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol 30(22):2718–2724CrossRefPubMedGoogle Scholar
  25. 25.
    Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F et al (2012) Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366(6):520–529CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Stephens PJ, Tarpey PS, Davies H, Van Loo P, Greenman C, Wedge DC, Nik-Zainal S, Martin S, Varela I, Bignell GR et al (2012) The landscape of cancer genes and mutational processes in breast cancer. Nature 486(7403):400–404CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Banerji S, Cibulskis K, Rangel-Escareno C, Brown KK, Carter SL, Frederick AM, Lawrence MS, Sivachenko AY, Sougnez C, Zou L et al (2012) Sequence analysis of mutations and translocations across breast cancer subtypes. Nature 486(7403):405–409CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Ramaswamy S, Ross KN, Lander ES, Golub TR (2003) A molecular signature of metastasis in primary solid tumors. Nat Genet 33(1):49–54CrossRefPubMedGoogle Scholar
  29. 29.
    Weigelt B, Hu Z, He X, Livasy C, Carey LA, Ewend MG, Glas AM, Perou CM, Van’t Veer LJ (2005) Molecular portraits and 70-gene prognosis signature are preserved throughout the metastatic process of breast cancer. Cancer Res 65(20):9155–9158CrossRefPubMedGoogle Scholar
  30. 30.
    Fidler IJ, Kripke ML (1977) Metastasis results from preexisting variant cells within a malignant tumor. Science 197(4306):893–895CrossRefPubMedGoogle Scholar
  31. 31.
    Poste G, Fidler IJ (1980) The pathogenesis of cancer metastasis. Nature 283(5743):139–146CrossRefPubMedGoogle Scholar
  32. 32.
    Li S, Shen D, Shao J, Crowder R, Liu W, Prat A, He X, Liu S, Hoog J, Lu C et al (2013) Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts. Cell Rep 4(6):1116–1130CrossRefPubMedGoogle Scholar
  33. 33.
    Cancer Genome Atlas N (2012) Comprehensive molecular portraits of human breast tumours. Nature 490(7418):61–70CrossRefGoogle Scholar
  34. 34.
    Veeraraghavan J, Tan Y, Cao XX, Kim JA, Wang X, Chamness GC, Maiti SN, Cooper LJ, Edwards DP, Contreras A et al (2014) Recurrent ESR1-CCDC170 rearrangements in an aggressive subset of oestrogen receptor-positive breast cancers. Nat Commun 5:4577CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Aguilar H, Sole X, Bonifaci N, Serra-Musach J, Islam A, Lopez-Bigas N, Mendez-Pertuz M, Beijersbergen RL, Lazaro C, Urruticoechea A et al (2010) Biological reprogramming in acquired resistance to endocrine therapy of breast cancer. Oncogene 29(45):6071–6083CrossRefPubMedGoogle Scholar
  36. 36.
    Holst F, Stahl PR, Ruiz C, Hellwinkel O, Jehan Z, Wendland M, Lebeau A, Terracciano L, Al-Kuraya K, Janicke F et al (2007) Estrogen receptor alpha (ESR1) gene amplification is frequent in breast cancer. Nat Genet 39(5):655–660CrossRefPubMedGoogle Scholar
  37. 37.
    Tomita S, Zhang Z, Nakano M, Ibusuki M, Kawazoe T, Yamamoto Y, Iwase H (2009) Estrogen receptor alpha gene ESR1 amplification may predict endocrine therapy responsiveness in breast cancer patients. Cancer Sci 100(6):1012–1017CrossRefPubMedGoogle Scholar
  38. 38.
    Nielsen KV, Ejlertsen B, Muller S, Moller S, Rasmussen BB, Balslev E, Laenkholm AV, Christiansen P, Mouridsen HT (2011) Amplification of ESR1 may predict resistance to adjuvant tamoxifen in postmenopausal patients with hormone receptor positive breast cancer. Breast Cancer Res Treat 127(2):345–355CrossRefPubMedGoogle Scholar
  39. 39.
    Brown LA, Hoog J, Chin SF, Tao Y, Zayed AA, Chin K, Teschendorff AE, Quackenbush JF, Marioni JC, Leung S et al (2008) ESR1 gene amplification in breast cancer: a common phenomenon? Nat Genet 40(7):806–807 author reply 810-802CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Moelans CB, Holst F, Hellwinkel O, Simon R, van Diest PJ (2013) ESR1 amplification in breast cancer by optimized RNase FISH: frequent but low-level and heterogeneous. PLoS One 8(12):e84189CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Roodi N, Bailey LR, Kao WY, Verrier CS, Yee CJ, Dupont WD, Parl FF (1995) Estrogen receptor gene analysis in estrogen receptor-positive and receptor-negative primary breast cancer. J Natl Cancer Inst 87(6):446–451CrossRefPubMedGoogle Scholar
  42. 42.
    Fuqua SA, Wiltschke C, Zhang QX, Borg A, Castles CG, Friedrichs WE, Hopp T, Hilsenbeck S, Mohsin S, O'Connell P et al (2000) A hypersensitive estrogen receptor-alpha mutation in premalignant breast lesions. Cancer Res 60(15):4026–4029PubMedGoogle Scholar
  43. 43.
    Herynk MH, Parra I, Cui Y, Beyer A, Wu MF, Hilsenbeck SG, Fuqua SA (2007) Association between the estrogen receptor alpha A908G mutation and outcomes in invasive breast cancer. Clin Cancer Res 13(11):3235–3243CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Conway K, Parrish E, Edmiston SN, Tolbert D, Tse CK, Geradts J, Livasy CA, Singh H, Newman B, Millikan RC (2005) The estrogen receptor-alpha A908G (K303R) mutation occurs at a low frequency in invasive breast tumors: results from a population-based study. Breast Cancer Res 7(6):R871–R880CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Conway K, Parrish E, Edmiston SN, Tolbert D, Tse CK, Moorman P, Newman B, Millikan RC (2007) Risk factors for breast cancer characterized by the estrogen receptor alpha A908G (K303R) mutation. Breast Cancer Res: BCR 9(3):R36CrossRefPubMedGoogle Scholar
  46. 46.
    Abbasi S, Rasouli M, Nouri M, Kalbasi S (2013) Association of estrogen receptor-alpha A908G (K303R) mutation with breast cancer risk. Int J Clin Exp Med 6(1):39–49PubMedGoogle Scholar
  47. 47.
    Zhang Z, Yamashita H, Toyama T, Omoto Y, Sugiura H, Hara Y, Haruki N, Kobayashi S, Iwase H (2003) Estrogen receptor alpha mutation (A-to-G transition at nucleotide 908) is not found in different types of breast lesions from Japanese women. Breast Cancer 10(1):70–73CrossRefPubMedGoogle Scholar
  48. 48.
    Tebbit CL, Bentley RC, Olson JA Jr, Marks JR (2004) Estrogen receptor alpha (ESR1) mutant A908G is not a common feature in benign and malignant proliferations of the breast. Genes Chromosomes Cancer 40(1):51–54CrossRefPubMedGoogle Scholar
  49. 49.
    Oesterreich S, Davidson NE (2013) The search for ESR1 mutations in breast cancer. Nat Genet 45(12):1415–1416CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Giordano C, Cui Y, Barone I, Ando S, Mancini MA, Berno V, Fuqua SA (2010) Growth factor-induced resistance to tamoxifen is associated with a mutation of estrogen receptor alpha and its phosphorylation at serine 305. Breast Cancer Res Treat 119(1):71–85CrossRefPubMedGoogle Scholar
  51. 51.
    Barone I, Brusco L, Fuqua SA (2010) Estrogen receptor mutations and changes in downstream gene expression and signaling. Clin Cancer Res 16(10):2702–2708CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Barone I, Cui Y, Herynk MH, Corona-Rodriguez A, Giordano C, Selever J, Beyer A, Ando S, Fuqua SA (2009) Expression of the K303R estrogen receptor-alpha breast cancer mutation induces resistance to an aromatase inhibitor via addiction to the PI3K/Akt kinase pathway. Cancer Res 69(11):4724–4732CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Barone I, Iacopetta D, Covington KR, Cui Y, Tsimelzon A, Beyer A, Ando S, Fuqua SA (2010) Phosphorylation of the mutant K303R estrogen receptor alpha at serine 305 affects aromatase inhibitor sensitivity. Oncogene 29(16):2404–2414CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Herynk MH, Hopp T, Cui Y, Niu A, Corona-Rodriguez A, Fuqua SA (2010) A hypersensitive estrogen receptor alpha mutation that alters dynamic protein interactions. Breast Cancer Res Treat 122(2):381–393CrossRefPubMedGoogle Scholar
  55. 55.
    Cui Y, Zhang M, Pestell R, Curran EM, Welshons WV, Fuqua SA (2004) Phosphorylation of estrogen receptor alpha blocks its acetylation and regulates estrogen sensitivity. Cancer Res 64(24):9199–9208CrossRefPubMedGoogle Scholar
  56. 56.
    Barone I, Catalano S, Gelsomino L, Marsico S, Giordano C, Panza S, Bonofiglio D, Bossi G, Covington KR, Fuqua SA et al (2012) Leptin mediates tumor-stromal interactions that promote the invasive growth of breast cancer cells. Cancer Res 72(6):1416–1427CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Zhang QX, Borg A, Wolf DM, Oesterreich S, Fuqua SA (1997) An estrogen receptor mutant with strong hormone-independent activity from a metastatic breast cancer. Cancer Res 57(7):1244–1249PubMedGoogle Scholar
  58. 58.
    Merenbakh-Lamin K, Ben-Baruch N, Yeheskel A, Dvir A, Soussan-Gutman L, Jeselsohn R, Yelensky R, Brown M, Miller VA, Sarid D et al (2013) D538G mutation in estrogen receptor-alpha: a novel mechanism for acquired endocrine resistance in breast cancer. Cancer Res 73(23):6856–6864CrossRefPubMedGoogle Scholar
  59. 59.
    Robinson DR, Wu YM, Vats P, Su F, Lonigro RJ, Cao X, Kalyana-Sundaram S, Wang R, Ning Y, Hodges L et al (2013) Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet 45(12):1446–1451CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Toy W, Shen Y, Won H, Green B, Sakr RA, Will M, Li Z, Gala K, Fanning S, King TA et al (2013) ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet 45(12):1439–1445CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    De Mattos-Arruda L, Weigelt B, Cortes J, Won HH, Ng CK, Nuciforo P, Bidard FC, Aura C, Saura C, Peg V et al (2014) Capturing intra-tumor genetic heterogeneity by de novo mutation profiling of circulating cell-free tumor DNA: a proof-of-principle. Ann Oncol 25(9):1729–1735CrossRefPubMedGoogle Scholar
  62. 62.
    Jeselsohn R, Yelensky R, Buchwalter G, Frampton G, Meric-Bernstam F, Gonzalez-Angulo AM, Ferrer-Lozano J, Perez-Fidalgo JA, Cristofanilli M, Gomez H et al (2014) Emergence of constitutively active estrogen receptor-alpha mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin Cancer Res 20(7):1757–1767CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Guttery DS, Page K, Hills A, Woodley L, Marchese SD, Rghebi B, Hastings RK, Luo J, Pringle JH, Stebbing J et al (2015) Noninvasive detection of activating estrogen receptor 1 (ESR1) mutations in estrogen receptor-positive metastatic breast cancer. Clin Chem 61(7):974–982CrossRefPubMedGoogle Scholar
  64. 64.
    Niu J, Andres G, Kramer K, Kundranda MN, Alvarez RH, Klimant E, Parikh AR, Tan B, Staren ED, Markman M (2015) Incidence and clinical significance of ESR1 mutations in heavily pretreated metastatic breast cancer patients. Onco Targets Ther 8:3323–3328CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Sefrioui D, Perdrix A, Sarafan-Vasseur N, Dolfus C, Dujon A, Picquenot JM, Delacour J, Cornic M, Bohers E, Leheurteur M et al (2015) Short report: Monitoring ESR1 mutations by circulating tumor DNA in aromatase inhibitor resistant metastatic breast cancer. Int J Cancer 137(10):2513–2519CrossRefPubMedGoogle Scholar
  66. 66.
    Schiavon G, Hrebien S, Garcia-Murillas I, Cutts RJ, Pearson A, Tarazona N, Fenwick K, Kozarewa I, Lopez-Knowles E, Ribas R et al (2015) Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer. Sci Transl Med 7(313):313ra182CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Takeshita T, Yamamoto Y, Yamamoto-Ibusuki M, Inao T, Sueta A, Fujiwara S, Omoto Y, Iwase H (2015) Droplet digital polymerase chain reaction assay for screening of ESR1 mutations in 325 breast cancer specimens. Transl Res 166(6):540–553 e542 CrossRefPubMedGoogle Scholar
  68. 68.
    Wang T, Liu JH, Zhang J, Wang L, Chen C, Dai PG (2015) A multiplex allele-specific real-time PCR assay for screening of ESR1 mutations in metastatic breast cancer. Exp Mol Pathol 98(2):152–157CrossRefPubMedGoogle Scholar
  69. 69.
    Chandarlapaty S, Chen D, He W, Sung P, Samoila A, You D, Bhatt T, Patel P, Voi M, Gnant M et al (2016) Prevalence of ESR1 mutations in cell-free DNA and outcomes in metastatic breast cancer: a secondary analysis of the BOLERO-2 clinical trial. JAMA Oncol 2(10):1310–1315CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Clatot F, Perdrix A, Augusto L, Beaussire L, Delacour J, Calbrix C, Sefrioui D, Viailly PJ, Bubenheim M, Moldovan C et al (2016) Kinetics, prognostic and predictive values of ESR1 circulating mutations in metastatic breast cancer patients progressing on aromatase inhibitor. Oncotarget 7(46):74448–74459CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Gyanchandani R, Kota KJ, Jonnalagadda AR, Minteer T, Knapick BA, Oesterreich S, Brufsky AM, Lee AV, Puhalla SL (2016) Detection of ESR1 mutations in circulating cell-free DNA from patients with metastatic breast cancer treated with palbociclib and letrozole. OncotargetGoogle Scholar
  72. 72.
    Hrebien S, O’Leary B, Beaney M, Schiavon G, Fribbens C, Bhambra A, Johnson R, Garcia-Murillas I, Turner N (2016) Reproducibility of digital PCR assays for circulating tumor DNA analysis in advanced breast cancer. PLoS One 11(10):e0165023CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Ma CX, Luo J, Naughton M, Ademuyiwa F, Suresh R, Griffith M, Griffith OL, Skidmore ZL, Spies NC, Ramu A et al (2016) A phase I trial of BKM120 (buparlisib) in combination with fulvestrant in postmenopausal women with estrogen receptor-positive metastatic breast cancer. Clin Cancer Res 22(7):1583–1591CrossRefPubMedGoogle Scholar
  74. 74.
    Spoerke JM, Gendreau S, Walter K, Qiu J, Wilson TR, Savage H, Aimi J, Derynck MK, Chen M, Chan IT et al (2016) Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant. Nat Commun 7:11579CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Takeshita T, Yamamoto Y, Yamamoto-Ibusuki M, Inao T, Sueta A, Fujiwara S, Omoto Y, Iwase H (2016) Clinical significance of monitoring ESR1 mutations in circulating cell-free DNA in estrogen receptor positive breast cancer patients. Oncotarget 7(22):32504–32518CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Wang P, Bahreini A, Gyanchandani R, Lucas PC, Hartmaier RJ, Watters RJ, Jonnalagadda AR, Trejo Bittar HE, Berg A, Hamilton RL et al (2016) Sensitive detection of mono- and polyclonal ESR1 mutations in primary tumors, metastatic lesions, and cell-free DNA of breast cancer patients. Clin Cancer Res 22(5):1130–1137CrossRefPubMedGoogle Scholar
  77. 77.
    Chu D, Paoletti C, Gersch C, VanDenBerg DA, Zabransky DJ, Cochran RL, Wong HY, Toro PV, Cidado J, Croessmann S et al (2016) ESR1 mutations in circulating plasma tumor DNA from metastatic breast cancer patients. Clin Cancer Res 22(4):993–999CrossRefPubMedGoogle Scholar
  78. 78.
    Fribbens C, O’Leary B, Kilburn L, Hrebien S, Garcia-Murillas I, Beaney M, Cristofanilli M, Andre F, Loi S, Loibl S et al (2016) Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer. J Clin Oncol 34(25):2961–2968CrossRefPubMedGoogle Scholar
  79. 79.
    Page K, Guttery DS, Fernandez-Garcia D, Hills A, Hastings RK, Luo J, Goddard K, Shahin V, Woodley-Barker L, Rosales BM et al (2017) Next generation sequencing of circulating cell-free DNA for evaluating mutations and gene amplification in metastatic breast cancer. Clin Chem 63(2):532–541CrossRefPubMedGoogle Scholar
  80. 80.
    Shaw JA, Guttery DS, Hills A, Fernandez-Garcia D, Page K, Rosales BM, Goddard KS, Hastings RK, Luo J, Ogle O et al (2017) Mutation analysis of cell-free DNA and single circulating tumor cells in metastatic breast cancer patients with high circulating tumor cell counts. Clin Cancer Res 23(1):88–96CrossRefPubMedGoogle Scholar
  81. 81.
    Gelsomino L, Gu G, Rechoum Y, Beyer AR, Pejerrey SM, Tsimelzon A, Wang T, Huffman K, Ludlow A, Ando S et al (2016) ESR1 mutations affect anti-proliferative responses to tamoxifen through enhanced cross-talk with IGF signaling. Breast Cancer Res Treat 157(2):253–265CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Lefebvre C, Bachelot T, Filleron T, Pedrero M, Campone M, Soria JC, Massard C, Levy C, Arnedos M, Lacroix-Triki M et al (2016) Mutational profile of metastatic breast cancers: a retrospective analysis. PLoS Med 13(12):e1002201CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    McIntyre JB, Rambau PF, Chan A, Yap S, Morris D, Nelson GS, Kobel M (2017) Molecular alterations in indolent, aggressive and recurrent ovarian low-grade serous carcinoma. Histopathology 70(3):347–358CrossRefPubMedGoogle Scholar
  84. 84.
    Arnold SF, Notides AC (1995) An antiestrogen: a phosphotyrosyl peptide that blocks dimerization of the human estrogen receptor. Proc Natl Acad Sci 92(16):7475–7479CrossRefPubMedGoogle Scholar
  85. 85.
    Jeselsohn R, Buchwalter G, De Angelis C, Brown M, Schiff R (2015) ESR1 mutations—a mechanism for acquired endocrine resistance in breast cancer. Nat Rev Clin Oncol 12(10):573–583CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Yu M, Bardia A, Aceto N, Bersani F, Madden MW, Donaldson MC, Desai R, Zhu H, Comaills V, Zheng Z et al (2014) Cancer therapy. Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility. Science 345(6193):216–220CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Gu G, Fuqua SA (2016) ESR1 mutations in breast cancer: proof-of-concept challenges clinical action. Clin Cancer Res 22(5):1034–1036CrossRefPubMedGoogle Scholar
  88. 88.
    Fumagalli D, Wilson TR, Salgado R, Lu X, Yu J, O’Brien C, Walter K, Huw LY, Criscitiello C, Laios I et al (2016) Somatic mutation, copy number and transcriptomic profiles of primary and matched metastatic estrogen receptor-positive breast cancers. Ann Oncol 27(10):1860–1866CrossRefPubMedGoogle Scholar
  89. 89.
    Miller CA, Gindin Y, Lu C, Griffith OL, Griffith M, Shen D, Hoog J, Li T, Larson DE, Watson M et al (2016) Aromatase inhibition remodels the clonal architecture of estrogen-receptor-positive breast cancers. Nat Commun 7:12498CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Garcia-Murillas I, Schiavon G, Weigelt B, Ng C, Hrebien S, Cutts RJ, Cheang M, Osin P, Nerurkar A, Kozarewa I et al (2015) Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Sci Transl Med 7(302):302ra133CrossRefPubMedGoogle Scholar
  91. 91.
    Fuqua SA, Rechoum Y, Gu G (2016) ESR1 mutations in cell-free DNA of breast cancer: predictive “tip of the iceberg”. JAMA Oncol 2(10):1315–1316CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Bartels S, Christgen M, Luft A, Persing S, Jodecke K, Lehmann U, Kreipe H (2017) Estrogen receptor (ESR1) mutation in bone metastases from breast cancer. Mod PatholGoogle Scholar
  93. 93.
    Harrod A, Fulton J, Nguyen VT, Periyasamy M, Ramos-Garcia L, Lai CF, Metodieva G, de Giorgio A, Williams RL, Santos DB et al (2016) Genomic modelling of the ESR1 Y537S mutation for evaluating function and new therapeutic approaches for metastatic breast cancer. OncogeneGoogle Scholar
  94. 94.
    Tormey DC, Lippman ME, Edwards BK, Cassidy JG (1983) Evaluation of tamoxifen doses with and without fluoxymesterone in advanced breast cancer. Ann Intern Med 98(2):139–144CrossRefPubMedGoogle Scholar
  95. 95.
    Paoletti C, Larios JM, Muniz MC, Aung K, Cannell EM, Darga EP, Kidwell KM, Thomas DG, Tokudome N, Brown ME et al (2016) Heterogeneous estrogen receptor expression in circulating tumor cells suggests diverse mechanisms of fulvestrant resistance. Mol Oncol 10(7):1078–1085CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Bardia A, Iafrate JA, Sundaresan T, Younger J, Nardi V (2016) Metastatic breast cancer with ESR1 mutation: clinical management considerations from the Molecular and Precision Medicine (MAP) Tumor Board at Massachusetts General Hospital. Oncologist 21(9):1035–1040CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Joseph JD, Darimont B, Zhou W, Arrazate A, Young A, Ingalla E, Walter K, Blake RA, Nonomiya J, Guan Z et al (2016) The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer. eLife 5Google Scholar
  98. 98.
    Weir HM, Bradbury RH, Lawson M, Rabow AA, Buttar D, Callis RJ, Curwen JO, de Almeida C, Ballard P, Hulse M et al (2016) AZD9496: an oral estrogen receptor inhibitor that blocks the growth of ER-positive and ESR1-mutant breast tumors in preclinical models. Cancer Res 76(11):3307–3318CrossRefPubMedGoogle Scholar
  99. 99.
    Wardell SE, Ellis MJ, Alley HM, Eisele K, VanArsdale T, Dann SG, Arndt KT, Primeau T, Griffin E, Shao J et al (2015) Efficacy of SERD/SERM hybrid-CDK4/6 inhibitor combinations in models of endocrine therapy-resistant breast cancer. Clin Cancer Res 21(22):5121–5130CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Lester and Sue Smith Breast CenterBaylor College of MedicineHoustonUSA

Personalised recommendations