Skip to main content
SpringerLink
Log in
Book cover

Resistance to Aromatase Inhibitors in Breast Cancer pp 191–228Cite as

Prediction of Response to Aromatase Inhibitors in Breast Cancer

  • Chapter
  • First Online:

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT,volume 8))

Abstract

Aromatase inhibitors (AIs) are major treatment options for the management of patients with breast cancer. The drugs are effective and response rates can be high. However, resistance, either primary or acquired during treatment, may occur. Optimal clinical management requires accurate predictors of response to identify those tumours, which are most likely to respond (so sparing patients with resistant tumours needless side-effects of ineffective therapy). Currently, oestrogen receptor (ER) status is the only factor used routinely to select for treatment with aromatase inhibitors, but a substantial proportion of ER-positive tumours fails treatment. There is, therefore, an urgent need to identify additional markers by which accurately to predict clinical response on an individual basis. Whilst other markers (such as progesterone receptors or HER2) have some predictive powers, individually they have limited utility for routine use. The hope is that discovery strategies based on genome-wide searches will identify novel markers that can be used as predictive indices. Molecular phenotyping of individual tumours could then be used to decide not only which patients should be treated with AIs but whether AIs should be used alone or in combination or in sequence with other targeted agents in order that clinical benefits are maximized. This chapter will focus on utility of routinely assessed biomarkers, multi-component indices and gene signatures and outline the future perspectives in studies aimed to AI response prediction.

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

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD   109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Abbreviations

AIs:

Aromatase inhibitors

ER:

Oestrogen receptor

PgR:

Progesterone receptor

ER+ve:

Oestrogen receptor positive

ER−ve:

Oestrogen receptor negative

pCR:

Complete pathological response

References

  1. Early Breast Cancer Trialists’ Collaborative G. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687–717.

    Google Scholar 

  2. Lonning PE, Eikesdal HP. Aromatase inhibition 2013: clinical state of the art and questions that remain to be solved. Endocr Relat Cancer. 2013;20(4):R183–201.

    PubMed Central  PubMed  Google Scholar 

  3. Miller WR. Aromatase inhibitors and breast cancer. Minerva Endocrinol. 2006;31(1):27–46.

    CAS  PubMed  Google Scholar 

  4. Dowsett M, Jones A, Johnston SR, Jacobs S, Trunet P, Smith IE. In vivo measurement of aromatase inhibition by letrozole (CGS 20267) in postmenopausal patients with breast cancer. Clin Cancer Res. 1995;1(12):1511–5.

    CAS  PubMed  Google Scholar 

  5. Geisler J, Haynes B, Anker G, Dowsett M, Lønning PE. Influence of letrozole (Femara) and anastrozole (Arimidex) on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, cross-over-designed study. J Clin Oncol. 2002;20:751–7.

    CAS  PubMed  Google Scholar 

  6. Ingle JN, Kr K, Buzdar AU, Robson ME, Goetz MP, Desta Z, Barman P, Dudenkov TT, Northfelt DW, Perez EA, Flockhart DA, Williard CV, Wang L, Weinshilboum RM. Estrogens and their precursors in postmenopausal women with early breast cancer receiving anastrozole. Steroids. 2014.

    Google Scholar 

  7. Dowsett M, Smith IE, Ebbs SR, Dixon JM, Skene A, Griffith C, Boeddinghaus I, Salter J, Detre S, Hills M, Ashley S, Francis S, Walsh G, Trialists I. Short-term changes in Ki-67 during neoadjuvant treatment of primary breast cancer with anastrozole or tamoxifen alone or combined correlate with recurrence-free survival. Clin Cancer Res. 2005;11(2 Pt 2):951s–8s.

    CAS  PubMed  Google Scholar 

  8. Ellis MJ, Coop A, Singh B, Tao Y, Llombart-Cussac A, Janicke F, Mauriac L, Quebe-Fehling E, Chaudri-Ross HA, Evans DB, Miller WR. Letrozole inhibits tumor proliferation more effectively than tamoxifen independent of HER1/2 expression status. Cancer Res. 2003;63(19):6523–31.

    CAS  PubMed  Google Scholar 

  9. Miller WR. Clinical, pathological, proliferative and molecular responses associated with neoadjuvant aromatase inhibitor treatment in breast cancer. J Steroid Biochem Mol Biol. 2010;118(4–5):273–6.

    CAS  PubMed  Google Scholar 

  10. Miller WR, Anderson TJ, Dixon JM. Anti-tumor effects of letrozole. Cancer Invest. 2002;20(2):15–21.

    CAS  PubMed  Google Scholar 

  11. Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A, Apffelstaedt J, Smith R, Sleeboom HP, Jaenicke F, Pluzanska A, Dank M, Becquart D, Bapsy PP, Salminen E, Snyder R, Chaudri-Ross H, Lang R, Wyld P, Bhatnagar A. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol. 2003;21(11):2101–9.

    CAS  PubMed  Google Scholar 

  12. Cuzick J, Sestak I, Baum M, Buzdar A, Howell A, Dowsett M, Forbes JF, investigators AL. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol. 2010;11(12):1135–41.

    CAS  PubMed  Google Scholar 

  13. Regan MM, Price KN, Giobbie-Hurder A, Thurlimann B, Gelber RD. International breast cancer study G, Group B I G C. Interpreting Breast International Group (BIG) 1-98: a randomized, double-blind, phase III trial comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive, early breast cancer. Breast Cancer Res. 2011;13(3):209.

    PubMed Central  CAS  PubMed  Google Scholar 

  14. van de Velde CJ, Rea D, Seynaeve C, Putter H, Hasenburg A, Vannetzel JM, Paridaens R, Markopoulos C, Hozumi Y, Hille ET, Kieback DG, Asmar L, Smeets J, Nortier JW, Hadji P, Bartlett JM, Jones SE. Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Lancet. 2011;377(9762):321–31.

    PubMed  Google Scholar 

  15. Eiermann W, Paepke S, Appfelstaedt J, Llombart-Cussac A, Eremin J, Vinholes J, Mauriac L, Ellis M, Lassus M, Chaudri-Ross HA, Dugan M, Borgs M. Letrozole neo-adjuvant breast cancer study G. Preoperative treatment of postmenopausal breast cancer patients with letrozole: a randomized double-blind multicenter study. Ann Oncol. 2001;12(11):1527–32.

    CAS  PubMed  Google Scholar 

  16. Ellis MJ, Ma C. Letrozole in the neoadjuvant setting: the P024 trial. Breast Cancer Res Treat. 2007;105(Suppl 1):33–43.

    PubMed Central  CAS  PubMed  Google Scholar 

  17. Charehbili A, Fontein DB, Kroep JR, Liefers GJ, Mieog JS, Nortier JW, van de Velde CJ. Neoadjuvant hormonal therapy for endocrine sensitive breast cancer: a systematic review. Cancer Treat Rev. 2014;40(1):86–92.

    CAS  PubMed  Google Scholar 

  18. Schiavon G, Smith IE. Endocrine therapy for advanced/metastatic breast cancer. Hematol Oncol Clin North Am. 2013;27(4):715–736, viii.

    Google Scholar 

  19. Milani A, Geuna E, Mittica G, Valabrega G. Overcoming endocrine resistance in metastatic breast cancer: current evidence and future directions. World J Clin Oncol. 2014;5(5):990–1001.

    PubMed Central  PubMed  Google Scholar 

  20. Aydiner A. Meta-analysis of breast cancer outcome and toxicity in adjuvant trials of aromatase inhibitors in postmenopausal women. Breast. 2013;22(2):121–9.

    PubMed  Google Scholar 

  21. Dowsett M, Cuzick J, Ingle J, Coates A, Forbes J, Bliss J, Buyse M, Baum M, Buzdar A, Colleoni M, Coombes C, Snowdon C, Gnant M, Jakesz R, Kaufmann M, Boccardo F, Godwin J, Davies C, Peto R. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol. 2010;28(3):509–18.

    CAS  PubMed  Google Scholar 

  22. Miller WR. Prediction of estrogen sensitivity/dependence. In: Miller WR, editor. Estrogen and breast cancer. Austin: R.G. Landes Co.; 1996. p. 151–170.

    Google Scholar 

  23. Saleh RR, Bouganim N, Hilton J, Arnaout A, Clemons M. Neoadjuvant endocrine treatment for breast cancer: from bedside to bench and back again? Curr Oncol. 2014;21(1):e122–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  24. Chia YH, Ellis MJ, Ma CX. Neoadjuvant endocrine therapy in primary breast cancer: indications and use as a research tool. Br J Cancer. 2010;103(6):759–64.

    PubMed Central  CAS  PubMed  Google Scholar 

  25. Miller WR, Larionov A, Anderson TJ, Evans DB, Dixon JM. Sequential changes in gene expression profiles in breast cancers during treatment with the aromatase inhibitor, letrozole. Pharmacogenomics J. 2012;12(1):10–21.

    CAS  PubMed  Google Scholar 

  26. Murray J, Miller WR, Dixon JM. Neoadjuvant endocrine therapy models. Methods Mol Med. 2006;120:489–502.

    PubMed  Google Scholar 

  27. Dixon JM, Renshaw L, Macaskill EJ, Young O, Murray J, Cameron D, Kerr GR, Evans DB, Miller WR. Increase in response rate by prolonged treatment with neoadjuvant letrozole. Breast Cancer Res Treat. 2009;113(1):145–51.

    CAS  PubMed  Google Scholar 

  28. Allevi G, Strina C, Andreis D, Zanoni V, Bazzola L, Bonardi S, Foroni C, Milani M, Cappelletti MR, Gussago F, Aguggini S, Giardini R, Martinotti M, Fox SB, Harris AL, Bottini A, Berruti A, Generali D. Increased pathological complete response rate after a long-term neoadjuvant letrozole treatment in postmenopausal oestrogen and/or progesterone receptor-positive breast cancer. Br J Cancer. 2013;108(8):1587–92.

    PubMed Central  CAS  PubMed  Google Scholar 

  29. Krainick-Strobel UE, Lichtenegger W, Wallwiener D, Tulusan AH, Janicke F, Bastert G, Kiesel L, Wackwitz B, Paepke S. Neoadjuvant letrozole in postmenopausal estrogen and/or progesterone receptor positive breast cancer: a phase IIb/III trial to investigate optimal duration of preoperative endocrine therapy. BMC Cancer. 2008;8:62.

    PubMed Central  PubMed  Google Scholar 

  30. Llombart-Cussac A, Guerrero A, Galan A, Caranana V, Buch E, Rodriguez-Lescure A, Ruiz A, Fuster Diana C, Guillem Porta V. Phase II trial with letrozole to maximum response as primary systemic therapy in postmenopausal patients with ER/PgR[+] operable breast cancer. Clin Transl Oncol. 2012;14(2):125–31.

    CAS  PubMed  Google Scholar 

  31. Goldhirsch A, Ingle JN, Gelber RD, Coates AS, Thurlimann B, Senn HJ, Panel M. Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2009. Ann Oncol. 2009;20(8):1319–29.

    PubMed Central  CAS  PubMed  Google Scholar 

  32. Goldhirsch A, Winer EP, Coates AS, Gelber RD, Piccart-Gebhart M, Thurlimann B, Senn HJ, Panel M. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol. 2013;24(9):2206–23.

    PubMed Central  CAS  PubMed  Google Scholar 

  33. Dowsett M. Preoperative models to evaluate endocrine strategies for breast cancer. Clin Cancer Res. 2003;9(1 Pt 2):502S–10S.

    CAS  PubMed  Google Scholar 

  34. Dowsett M, Smith IE, Ebbs SR, Dixon JM, Skene A, A’Hern R, Salter J, Detre S, Hills M, Walsh G, Group IT. Prognostic value of Ki67 expression after short-term presurgical endocrine therapy for primary breast cancer. J Natl Cancer Inst. 2007;99(2):167–170.

    Google Scholar 

  35. Mackay A, Urruticoechea A, Dixon JM, Dexter T, Fenwick K, Ashworth A, Drury S, Larionov A, Young O, White S, Miller WR, Evans DB, Dowsett M. Molecular response to aromatase inhibitor treatment in primary breast cancer. Breast Cancer Res. 2007;9(3):R37.

    PubMed Central  PubMed  Google Scholar 

  36. Bedard PL, Singhal SK, Ignatiadis M, Bradbury I, Haibe-Kains B, Desmedt C, Loi S, Evans DB, Michiels S, Dixon JM, Miller WR, Piccart MJ, Sotiriou C. Low residual proliferation after short-term letrozole therapy is an early predictive marker of response in high proliferative ER-positive breast cancer. Endocr Relat Cancer. 2011;18(6):721–30.

    CAS  PubMed  Google Scholar 

  37. Dixon JM, Renshaw L, Bellamy C, Stuart M, Hoctin-Boes G, Miller WR. The effects of neoadjuvant anastrozole (Arimidex) on tumor volume in postmenopausal women with breast cancer: a randomized, double-blind, single-center study. Clin Cancer Res. 2000;6(6):2229–35.

    CAS  PubMed  Google Scholar 

  38. Tao Y, Klause A, Vickers A, Bae K, Ellis M. Clinical and biomarker endpoint analysis in neoadjuvant endocrine therapy trials. J Steroid Biochem Mol Biol. 2005;95(1–5):91–5.

    CAS  PubMed  Google Scholar 

  39. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer. 1981;47(1):207–14.

    CAS  PubMed  Google Scholar 

  40. Therasse P, Eisenhauer EA, Verweij J. RECIST revisited: a review of validation studies on tumour assessment. Eur J Cancer. 2006;42(8):1031–9.

    CAS  PubMed  Google Scholar 

  41. Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, Bonnefoi H, Cameron D, Gianni L, Valagussa P, Swain SM, Prowell T, Loibl S, Wickerham DL, Bogaerts J, Baselga J, Perou C, Blumenthal G, Blohmer J, Mamounas EP, Bergh J, Semiglazov V, Justice R, Eidtmann H, Paik S, Piccart M, Sridhara R, Fasching PA, Slaets L, Tang S, Gerber B, Jr Geyer CE, Pazdur R, Ditsch N, Rastogi P, Eiermann W, von Minckwitz G. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384(9938):164–72.

    PubMed  Google Scholar 

  42. FDA. Guidance for industry: pathological complete response in neoadjuvant treatment of high-risk early-stage breast cancer: use as an endpoint to support accelerated approval. 2014.

    Google Scholar 

  43. von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, Gerber B, Eiermann W, Hilfrich J, Huober J, Jackisch C, Kaufmann M, Konecny GE, Denkert C, Nekljudova V, Mehta K, Loibl S. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol. 2012;30(15):1796–804.

    Google Scholar 

  44. Abrial C, Mouret-Reynier MA, Cure H, Feillel V, Leheurteur M, Lemery S, Le Bouedec G, Durando X, Dauplat J, Chollet P. Neoadjuvant endocrine therapy in breast cancer. Breast. 2006;15(1):9–19.

    CAS  PubMed  Google Scholar 

  45. Thomas JS, Julian HS, Green RV, Cameron DA, Dixon MJ. Histopathology of breast carcinoma following neoadjuvant systemic therapy: a common association between letrozole therapy and central scarring. Histopathology. 2007;51(2):219–26.

    CAS  PubMed  Google Scholar 

  46. Miller WR, White S, Dixon JM, Murray J, Renshaw L, Anderson TJ. Proliferation, steroid receptors and clinical/pathological response in breast cancer treated with letrozole. Br J Cancer. 2006;94(7):1051–6.

    PubMed Central  CAS  PubMed  Google Scholar 

  47. Miller WR, Larionov A. Molecular effects of oestrogen deprivation in breast cancer. Mol Cell Endocrinol. 2011;340(2):127–36.

    CAS  PubMed  Google Scholar 

  48. Miller WR, Larionov A, Renshaw L, Anderson TJ, Walker JR, Krause A, Sing T, Evans DB, Dixon JM. Gene expression profiles differentiating between breast cancers clinically responsive or resistant to letrozole. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2009;27(9):1382–7.

    CAS  Google Scholar 

  49. Urruticoechea A, Smith IE, Dowsett M. Proliferation marker Ki-67 in early breast cancer. J Clin Oncol. 2005;23(28):7212–20.

    CAS  PubMed  Google Scholar 

  50. Ma CX, Sanchez CG, Ellis MJ. Predicting endocrine therapy responsiveness in breast cancer. Oncology. 2009;23(2):133–42 (Williston Park).

    PubMed  Google Scholar 

  51. Beresford M, Tumur I, Chakrabarti J, Barden J, Rao N, Makris A. A qualitative systematic review of the evidence base for non-cross-resistance between steroidal and non-steroidal aromatase inhibitors in metastatic breast cancer. Clin Oncol (R Coll Radiol). 2011;23(3):209–15.

    CAS  Google Scholar 

  52. Itoh T, Karlsberg K, Kijima I, Yuan YC, Smith D, Ye J, Chen S. Letrozole-, anastrozole-, and tamoxifen-responsive genes in MCF-7aro cells: a microarray approach. Mol Cancer Res. 2005;3(4):203–18.

    CAS  PubMed  Google Scholar 

  53. Pepe MS, Etzioni R, Feng Z, Potter JD, Thompson ML, Thornquist M, Winget M, Yasui Y. Phases of biomarker development for early detection of cancer. J Natl Cancer Inst. 2001;93(14):1054–61.

    CAS  PubMed  Google Scholar 

  54. Hayes DF, Bast RC, Desch CE, Fritsche H Jr, Kemeny NE, Jessup JM, Locker GY, Macdonald JS, Mennel RG, Norton L, Ravdin P, Taube S, Winn RJ. Tumor marker utility grading system: a framework to evaluate clinical utility of tumor markers. J Natl Cancer Inst. 1996;88(20):1456–66.

    CAS  PubMed  Google Scholar 

  55. Bogaerts J, Cardoso F, Buyse M, Braga S, Loi S, Harrison JA, Bines J, Mook S, Decker N, Ravdin P, Therasse P, Rutgers E, van ‘t Veer LJ, Piccart M, consortium T. Gene signature evaluation as a prognostic tool: challenges in the design of the MINDACT trial. Nat Clin Pract Oncol. 2006;3(10):540–551.

    Google Scholar 

  56. Sparano JA. TAILORx: trial assigning individualized options for treatment (Rx). Clin Breast Cancer. 2006;7(4):347–50.

    PubMed  Google Scholar 

  57. Simon RM, Paik S, Hayes DF. Use of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst. 2009;101(21):1446–52.

    PubMed Central  PubMed  Google Scholar 

  58. Dowsett M, Allred C, Knox J, Quinn E, Salter J, Wale C, Cuzick J, Houghton J, Williams N, Mallon E, Bishop H, Ellis I, Larsimont D, Sasano H, Carder P, Cussac AL, Knox F, Speirs V, Forbes J, Buzdar A. Relationship between quantitative estrogen and progesterone receptor expression and human epidermal growth factor receptor 2 (HER-2) status with recurrence in the Arimidex, Tamoxifen, alone or in combination trial. J Clin Oncol. 2008;26(7):1059–65.

    CAS  PubMed  Google Scholar 

  59. Fiorito E, Katika MR, Hurtado A. Cooperating transcription factors mediate the function of estrogen receptor. Chromosoma. 2013;122(1–2):1–12.

    PubMed Central  CAS  PubMed  Google Scholar 

  60. Elledge RM, Osborne CK. Oestrogen receptors and breast cancer. BMJ. 1997;314(7098):1843–4.

    PubMed Central  CAS  PubMed  Google Scholar 

  61. Ellis MJ, Coop A, Singh B, Mauriac L, Llombert-Cussac A, Janicke F, Miller WR, Evans DB, Dugan M, Brady C, Quebe-Fehling E, Borgs M. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial. J Clin Oncol. 2001;19(18):3808–16.

    CAS  PubMed  Google Scholar 

  62. Buzdar AU, Vergote I, Sainsbury R. The impact of hormone receptor status on the clinical efficacy of the new-generation aromatase inhibitors: a review of data from first-line metastatic disease trials in postmenopausal women. Breast J. 2004;10(3):211–7.

    CAS  PubMed  Google Scholar 

  63. Anderson H, Hills M, Zabaglo L, A’Hern R, Leary AF, Haynes BP, Smith IE, Dowsett M. Relationship between estrogen receptor, progesterone receptor, HER-2 and Ki67 expression and efficacy of aromatase inhibitors in advanced breast cancer. Ann Oncol. 2011;22(8):1770–6.

    CAS  PubMed  Google Scholar 

  64. Nassar A, Radhakrishnan A, Cabrero IA, Cotsonis GA, Cohen C. Intratumoral heterogeneity of immunohistochemical marker expression in breast carcinoma: a tissue microarray-based study. Appl Immunohistochem Mol Morphol. 2010;18(5):433–41.

    CAS  PubMed  Google Scholar 

  65. Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M, Hicks DG, Lester S, Love R, Mangu PB, McShane L, Miller K, Osborne CK, Paik S, Perlmutter J, Rhodes A, Sasano H, Schwartz JN, Sweep FC, Taube S, Torlakovic EE, Valenstein P, Viale G, Visscher D, Wheeler T, Williams RB, Wittliff JL, Wolff AC. 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. 2010;28(16):2784–95.

    PubMed Central  PubMed  Google Scholar 

  66. Harvey JM, Clark GM, Osborne CK, Allred DC. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol. 1999;17(5):1474–81.

    CAS  PubMed  Google Scholar 

  67. Brouckaert O, Paridaens R, Floris G, Rakha E, Osborne K, Neven P. A critical review why assessment of steroid hormone receptors in breast cancer should be quantitative. Ann Oncol. 2013;24(1):47–53.

    CAS  PubMed  Google Scholar 

  68. Prabhu JS, Korlimarla A, Desai K, Alexander A, Raghavan R, Anupama C, Dendukuri N, Manjunath S, Correa M, Raman N, Kalamdani A, Prasad M, Gopinath KS, Srinath BS, Sridhar TS. A majority of low (1-10 %) ER positive breast cancers behave like hormone receptor negative tumors. J Cancer. 2014;5(2):156–65.

    PubMed Central  CAS  PubMed  Google Scholar 

  69. Iwamoto T, Booser D, Valero V, Murray JL, Koenig K, Esteva FJ, Ueno NT, Zhang J, Shi W, Qi Y, Matsuoka J, Yang EJ, Hortobagyi GN, Hatzis C, Symmans WF, Pusztai L. Estrogen receptor (ER) mRNA and ER-related gene expression in breast cancers that are 1 % to 10 % ER-positive by immunohistochemistry. J Clin Oncol. 2012;30(7):729–34.

    PubMed  Google Scholar 

  70. Viale G, Regan MM, Maiorano E, Mastropasqua MG, Dell’Orto P, Rasmussen BB, Raffoul J, Neven P, Orosz Z, Braye S, Ohlschlegel C, Thurlimann B, Gelber RD, Castiglione-Gertsch M, Price KN, Goldhirsch A, Gusterson BA, Coates AS. Prognostic and predictive value of centrally reviewed expression of estrogen and progesterone receptors in a randomized trial comparing letrozole and tamoxifen adjuvant therapy for postmenopausal early breast cancer: BIG 1-98. J Clin Oncol. 2007;25(25):3846–52.

    PubMed  Google Scholar 

  71. Horwitz KB, McGuire WL. Predicting response to endocrine therapy in human breast cancer: a hypothesis. Science. 1975;189(4204):726–7.

    CAS  PubMed  Google Scholar 

  72. Hefti MM, Hu R, Knoblauch NW, Collins LC, Haibe-Kains B, Tamimi RM, Beck AH. Estrogen receptor negative/progesterone receptor positive breast cancer is not a reproducible subtype. Breast Cancer Res. 2013;15(4):R68.

    PubMed Central  PubMed  Google Scholar 

  73. Bardou VJ, Arpino G, Elledge RM, Osborne CK, Clark GM. Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases. J Clin Oncol. 2003;21(10):1973–9.

    CAS  PubMed  Google Scholar 

  74. Dunnwald LK, Rossing MA, Li CI. Hormone receptor status, tumor characteristics, and prognosis: a prospective cohort of breast cancer patients. Breast Cancer Res. 2007;9(1):R6.

    PubMed Central  PubMed  Google Scholar 

  75. Ponzone R, Montemurro F, Maggiorotto F, Robba C, Gregori D, Jacomuzzi ME, Kubatzki F, Marenco D, Dominguez A, Biglia N, Sismondi P. Clinical outcome of adjuvant endocrine treatment according to PR and HER-2 status in early breast cancer. Ann Oncol. 2006;17(11):1631–6.

    CAS  PubMed  Google Scholar 

  76. Dowsett M, Ebbs SR, Dixon JM, Skene A, Griffith C, Boeddinghaus I, Salter J, Detre S, Hills M, Ashley S, Francis S, Walsh G, Smith IE. Biomarker changes during neoadjuvant anastrozole, tamoxifen, or the combination: influence of hormonal status and HER-2 in breast cancer–a study from the IMPACT trialists. J Clin Oncol. 2005;23(11):2477–92.

    CAS  PubMed  Google Scholar 

  77. Ellis MJ, Tao Y, Young O, White S, Proia AD, Murray J, Renshaw L, Faratian D, Thomas J, Dowsett M, Krause A, Evans DB, Miller WR, Dixon JM. Estrogen-independent proliferation is present in estrogen-receptor HER2-positive primary breast cancer after neoadjuvant letrozole. J Clin Oncol. 2006;24(19):3019–25.

    CAS  PubMed  Google Scholar 

  78. Dowsett M, Harper-Wynne C, Boeddinghaus I, Salter J, Hills M, Dixon M, Ebbs S, Gui G, Sacks N, Smith I. HER-2 amplification impedes the antiproliferative effects of hormone therapy in estrogen receptor-positive primary breast cancer. Cancer Res. 2001;61(23):8452–8.

    CAS  PubMed  Google Scholar 

  79. Dixon JM, Jackson J, Hills M, Renshaw L, Cameron DA, Anderson TJ, Miller WR, Dowsett M. Anastrozole demonstrates clinical and biological effectiveness in oestrogen receptor-positive breast cancers, irrespective of the erbB2 status. Eur J Cancer. 2004;40(18):2742–7.

    CAS  PubMed  Google Scholar 

  80. Miller WR. ERBB2 status and outcome of endocrine treatment. Lancet Oncol. 2008;9(1):4–5.

    CAS  PubMed  Google Scholar 

  81. Dowsett M, Cuzick J, Wale C, Howell T, Houghton J, Baum M. Retrospective analysis of time to recurrence in the ATAC trial according to hormone receptor status: an hypothesis-generating study. J Clin Oncol. 2005;23(30):7512–7.

    CAS  PubMed  Google Scholar 

  82. Rasmussen BB, Regan MM, Lykkesfeldt AE, Dell’Orto P, Del Curto B, Henriksen KL, Mastropasqua MG, Price KN, Mery E, Lacroix-Triki M, Braye S, Altermatt HJ, Gelber RD, Castiglione-Gertsch M, Goldhirsch A, Gusterson BA, Thurlimann B, Coates AS, Viale G, Collaborative BIG. International Breast Cancer Study G. Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG 1-98 randomised trial. Lancet Oncol. 2008;9(1):23–8.

    CAS  PubMed  Google Scholar 

  83. Lal P, Tan LK, Chen B. Correlation of HER-2 status with estrogen and progesterone receptors and histologic features in 3,655 invasive breast carcinomas. Am J Clin Pathol. 2005;123(4):541–6.

    CAS  PubMed  Google Scholar 

  84. Gerdes J, Schwab U, Lemke H, Stein H. Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation. Int J Cancer. 1983;31(1):13–20.

    CAS  PubMed  Google Scholar 

  85. Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H. Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol. 1984;133(4):1710–5.

    CAS  PubMed  Google Scholar 

  86. Gerdes J. Ki-67 and other proliferation markers useful for immunohistological diagnostic and prognostic evaluations in human malignancies. Semin Cancer Biol. 1990;1(3):199–206.

    CAS  PubMed  Google Scholar 

  87. Lopez F, Belloc F, Lacombe F, Dumain P, Reiffers J, Bernard P, Boisseau MR. Modalities of synthesis of Ki67 antigen during the stimulation of lymphocytes. Cytometry. 1991;12(1):42–9.

    CAS  PubMed  Google Scholar 

  88. Endl E, Gerdes J. The Ki-67 protein: fascinating forms and an unknown function. Exp Cell Res. 2000;257(2):231–7.

    CAS  PubMed  Google Scholar 

  89. Scholzen T, Gerdes J. The Ki-67 protein: from the known and the unknown. J Cell Physiol. 2000;182(3):311–22.

    CAS  PubMed  Google Scholar 

  90. Brown DC, Gatter KC. Ki67 protein: the immaculate deception? Histopathology. 2002;40(1):2–11.

    CAS  PubMed  Google Scholar 

  91. Cheutin T, O’Donohue MF, Beorchia A, Klein C, Kaplan H, Ploton D. Three-dimensional organization of pKi-67: a comparative fluorescence and electron tomography study using FluoroNanogold. J Histochem Cytochem. 2003;51(11):1411–23.

    PubMed Central  CAS  PubMed  Google Scholar 

  92. Li H, Byeon IJ, Ju Y, Tsai MD. Structure of human Ki67 FHA domain and its binding to a phosphoprotein fragment from hNIFK reveal unique recognition sites and new views to the structural basis of FHA domain functions. J Mol Biol. 2004;335(1):371–81.

    CAS  PubMed  Google Scholar 

  93. Byeon IJ, Li H, Song H, Gronenborn AM, Tsai MD. Sequential phosphorylation and multisite interactions characterize specific target recognition by the FHA domain of Ki67. Nat Struct Mol Biol. 2005;12(11):987–93.

    CAS  PubMed  Google Scholar 

  94. Bullwinkel J, Baron-Luhr B, Ludemann A, Wohlenberg C, Gerdes J, Scholzen T. Ki-67 protein is associated with ribosomal RNA transcription in quiescent and proliferating cells. J Cell Physiol. 2006;206(3):624–35.

    CAS  PubMed  Google Scholar 

  95. Rahmanzadeh R, Huttmann G, Gerdes J, Scholzen T. Chromophore-assisted light inactivation of pKi-67 leads to inhibition of ribosomal RNA synthesis. Cell Prolif. 2007;40(3):422–30.

    CAS  PubMed  Google Scholar 

  96. van Diest PJ, van der Wall E, Baak JP. Prognostic value of proliferation in invasive breast cancer: a review. J Clin Pathol. 2004;57(7):675–81.

    PubMed Central  PubMed  Google Scholar 

  97. Cheang MC, Chia SK, Voduc D, Gao D, Leung S, Snider J, Watson M, Davies S, Bernard PS, Parker JS, Perou CM, Ellis MJ, Nielsen TO. Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst. 2009;101(10):736–50.

    PubMed Central  CAS  PubMed  Google Scholar 

  98. Schena M, Shalon D, Davis RW, Brown PO. Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science. 1995;270(5235):467–70.

    CAS  PubMed  Google Scholar 

  99. Kronick MN. Creation of the whole human genome microarray. Expert Rev Proteomics. 2004;1(1):19–28.

    CAS  PubMed  Google Scholar 

  100. Golub TR, Slonim DK, Tamayo P, Huard C, Gaasenbeek M, Mesirov JP, Coller H, Loh ML, Downing JR, Caligiuri MA, Bloomfield CD, Lander ES. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science. 1999;286(5439):531–7.

    CAS  PubMed  Google Scholar 

  101. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO, Botstein D. Molecular portraits of human breast tumours. Nature. 2000;406(6797):747–52.

    CAS  PubMed  Google Scholar 

  102. Eisen MB, Spellman PT, Brown PO, Botstein D. Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA. 1998;95(25):14863–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  103. Werner T. Bioinformatics applications for pathway analysis of microarray data. Curr Opin Biotechnol. 2008;19(1):50–4.

    CAS  PubMed  Google Scholar 

  104. Steinhoff C, Vingron M. Normalization and quantification of differential expression in gene expression microarrays. Brief Bioinform. 2006;7(2):166–77.

    CAS  PubMed  Google Scholar 

  105. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Roy Stat Soc: Ser B (Methodol). 1995;57(1):289–300.

    Google Scholar 

  106. Bonferroni CE. Il calcolo delle assicurazioni su gruppi di teste, in Studi in Onore del Professore Salvatore Ortu Carboni. 1935: Rome. p. 13–60.

    Google Scholar 

  107. Rice TK, Schork NJ, Rao DC. Methods for handling multiple testing. Adv Genet. 2008;60:293–308.

    PubMed  Google Scholar 

  108. Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, Baehner FL, Walker MG, Watson D, Park T, Hiller W, Fisher ER, Wickerham DL, Bryant J, Wolmark N. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351(27):2817–26.

    CAS  PubMed  Google Scholar 

  109. Filipits M, Rudas M, Jakesz R, Dubsky P, Fitzal F, Singer CF, Dietze O, Greil R, Jelen A, Sevelda P, Freibauer C, Muller V, Janicke F, Schmidt M, Kolbl H, Rody A, Kaufmann M, Schroth W, Brauch H, Schwab M, Fritz P, Weber KE, Feder IS, Hennig G, Kronenwett R, Gehrmann M, Gnant M, Investigators EP. A new molecular predictor of distant recurrence in ER-positive, HER2-negative breast cancer adds independent information to conventional clinical risk factors. Clin Cancer Res. 2011;17(18):6012–20.

    CAS  PubMed  Google Scholar 

  110. Parker JS, Mullins M, Cheang MC, Leung S, Voduc D, Vickery T, Davies S, Fauron C, He X, Hu Z, Quackenbush JF, Stijleman IJ, Palazzo J, Marron JS, Nobel AB, Mardis E, Nielsen TO, Ellis MJ, Perou CM, Bernard PS. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol. 2009;27(8):1160–7.

    PubMed Central  PubMed  Google Scholar 

  111. Ressom HW, Varghese RS, Zhang Z, Xuan J, Clarke R. Classification algorithms for phenotype prediction in genomics and proteomics. Frontiers in Bioscience : A Journal and Virtual Library. 2008;13:691–708.

    CAS  Google Scholar 

  112. Ransohoff DF. Rules of evidence for cancer molecular-marker discovery and validation. Nat Rev Cancer. 2004;4(4):309–14.

    CAS  PubMed  Google Scholar 

  113. Molinaro AM, Simon R, Pfeiffer RM. Prediction error estimation: a comparison of resampling methods. Bioinformatics. 2005;21(15):3301–7.

    CAS  PubMed  Google Scholar 

  114. Skates SJ. A statistical challenge: developing tests for biomarker utility specific to the intended use. J Natl Cancer Inst. 2014;106(4):dju076.

    Google Scholar 

  115. Sargent DJ, Mandrekar SJ. Statistical issues in the validation of prognostic, predictive, and surrogate biomarkers. Clin Trials. 2013;10(5):647–52.

    PubMed  Google Scholar 

  116. Sargent DJ, Conley BA, Allegra C, Collette L. Clinical trial designs for predictive marker validation in cancer treatment trials. J Clin Oncol. 2005;23(9):2020–7.

    PubMed  Google Scholar 

  117. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Lonning PE, Borresen-Dale AL. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001;98(19):10869–74.

    PubMed Central  CAS  PubMed  Google Scholar 

  118. Cancer Genome Atlas. N. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70.

    Google Scholar 

  119. Ades F, Zardavas D, Bozovic-Spasojevic I, Pugliano L, Fumagalli D, de Azambuja E, Viale G, Sotiriou C, Piccart M. Luminal B breast cancer: molecular characterization, clinical management, and future perspectives. J Clin Oncol. 2014;32(25):2794–803.

    PubMed  Google Scholar 

  120. Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thurlimann B, Senn HJ, Panel M. Strategies for subtypes–dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol. 2011;22(8):1736–47.

    PubMed Central  CAS  PubMed  Google Scholar 

  121. Ellis MJ, Suman VJ, Hoog J, Lin L, Snider J, Prat A, Parker JS, Luo J, DeSchryver K, Allred DC, Esserman LJ, Unzeitig GW, Margenthaler J, Babiera GV, Marcom PK, Guenther JM, Watson MA, Leitch M, Hunt K, Olson JA. Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype–ACOSOG Z1031. J Clin Oncol. 2011;29(17):2342–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  122. Dunbier AK, Anderson H, Ghazoui Z, Salter J, Parker JS, Perou CM, Smith IE, Dowsett M. Association between breast cancer subtypes and response to neoadjuvant anastrozole. Steroids. 2011;76(8):736–40.

    CAS  PubMed  Google Scholar 

  123. Smith IE, Walsh G, Skene A, Llombart A, Mayordomo JI, Detre S, Salter J, Clark E, Magill P, Dowsett M. A phase II placebo-controlled trial of neoadjuvant anastrozole alone or with gefitinib in early breast cancer. J Clin Oncol. 2007;25(25):3816–22.

    CAS  PubMed  Google Scholar 

  124. Harbeck N, Sotlar K, Wuerstlein R, Doisneau-Sixou S. Molecular and protein markers for clinical decision making in breast cancer: today and tomorrow. Cancer Treat Rev. 2014;40(3):434–44.

    CAS  PubMed  Google Scholar 

  125. Paik S, Tang G, Shak S, Kim C, Baker J, Kim W, Cronin M, Baehner FL, Watson D, Bryant J, Costantino JP, Jr Geyer CE, Wickerham DL, Wolmark N. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24(23):3726–34.

    CAS  PubMed  Google Scholar 

  126. Carlson JJ, Roth JA. The impact of the oncotype DX breast cancer assay in clinical practice: a systematic review and meta-analysis. Breast Cancer Res Treat. 2013;141(1):13–22.

    PubMed Central  PubMed  Google Scholar 

  127. Ueno T, Masuda N, Yamanaka T, Saji S, Kuroi K, Sato N, Takei H, Yamamoto Y, Ohno S, Yamashita H, Hisamatsu K, Aogi K, Iwata H, Sasano H, Toi M. Evaluating the 21-gene assay recurrence score(R) as a predictor of clinical response to 24 weeks of neoadjuvant exemestane in estrogen receptor-positive breast cancer. Int J Clin Oncol. 2014;19(4):607–13.

    CAS  PubMed  Google Scholar 

  128. Allison KH, Kandalaft PL, Sitlani CM, Dintzis SM, Gown AM. Routine pathologic parameters can predict oncotype DX recurrence scores in subsets of ER positive patients: who does not always need testing? Breast Cancer Res Treat. 2012;131(2):413–24.

    CAS  PubMed  Google Scholar 

  129. Milburn M, Rosman M, Mylander C, Tafra L. Is oncotype DX recurrence score (RS) of prognostic value once HER2-positive and. low-ER expression patients are removed? Breast J. 2013;19(4):357–64.

    PubMed  Google Scholar 

  130. Symmans WF, Hatzis C, Sotiriou C, Andre F, Peintinger F, Regitnig P, Daxenbichler G, Desmedt C, Domont J, Marth C, Delaloge S, Bauernhofer T, Valero V, Booser DJ, Hortobagyi GN, Pusztai L. Genomic index of sensitivity to endocrine therapy for breast cancer. J Clin Oncol. 2010;28(27):4111–9.

    PubMed Central  PubMed  Google Scholar 

  131. Kronenwett R, Bohmann K, Prinzler J, Sinn BV, Haufe F, Roth C, Averdick M, Ropers T, Windbergs C, Brase JC, Weber KE, Fisch K, Muller BM, Schmidt M, Filipits M, Dubsky P, Petry C, Dietel M, Denkert C. Decentral gene expression analysis: analytical validation of the endopredict genomic multianalyte breast cancer prognosis test. BMC Cancer. 2012;12:456.

    PubMed Central  CAS  PubMed  Google Scholar 

  132. Muller BM, Keil E, Lehmann A, Winzer KJ, Richter-Ehrenstein C, Prinzler J, Bangemann N, Reles A, Stadie S, Schoenegg W, Eucker J, Schmidt M, Lippek F, Johrens K, Pahl S, Sinn BV, Budczies J, Dietel M, Denkert C. The endopredict gene-expression assay in clinical practice—performance and impact on clinical decisions. PLoS ONE. 2013;8(6):e68252.

    PubMed Central  PubMed  Google Scholar 

  133. Ravdin PM, Siminoff LA, Davis GJ, Mercer MB, Hewlett J, Gerson N, Parker HL. Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer. J Clin Oncol. 2001;19(4):980–91.

    CAS  PubMed  Google Scholar 

  134. Wishart GC, Azzato EM, Greenberg DC, Rashbass J, Kearins O, Lawrence G, Caldas C, Pharoah PD. PREDICT: a new UK prognostic model that predicts survival following surgery for invasive breast cancer. Breast Cancer Res. 2010;12(1):R1.

    PubMed Central  PubMed  Google Scholar 

  135. Haybittle JL, Blamey RW, Elston CW, Johnson J, Doyle PJ, Campbell FC, Nicholson RI, Griffiths K. A prognostic index in primary breast cancer. Br J Cancer. 1982;45(3):361–6.

    PubMed Central  CAS  PubMed  Google Scholar 

  136. Ellis MJ, Tao Y, Luo J, A’Hern R, Evans DB, Bhatnagar AS, Chaudri Ross HA, von Kameke A, Miller WR, Smith I, Eiermann W, Dowsett M. Outcome prediction for estrogen receptor-positive breast cancer based on postneoadjuvant endocrine therapy tumor characteristics. J Natl Cancer Inst. 2008;100(19):1380–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  137. Ravdin PM, Davis GJ. A method for making estimates of the benefit of the late use of letrozole in patients completing 5 years of tamoxifen. Clin Breast Cancer. 2004;5(4):313–6.

    CAS  PubMed  Google Scholar 

  138. Smith IE, Dowsett M, Ebbs SR, Dixon JM, Skene A, Blohmer JU, Ashley SE, Francis S, Boeddinghaus I, Walsh G, Group IT. Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol. (2005);23(22):5108–16.

    Google Scholar 

  139. Goncalves R, Ma C, Luo J, Suman V, Ellis MJ. Use of neoadjuvant data to design adjuvant endocrine therapy trials for breast cancer. Nat Rev Clin Oncol. 2012;9(4):223–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  140. Cleator SJ, Makris A, Ashley SE, Lal R, Powles TJ. Good clinical response of breast cancers to neoadjuvant chemoendocrine therapy is associated with improved overall survival. Ann Oncol. 2005;16(2):267–72.

    CAS  PubMed  Google Scholar 

  141. Akashi-Tanaka S, Omatsu M, Shimizu C, Ando M, Terada K, Shien T, Kinoshita T, Fujiwara Y, Seki K, Hasegawa T, Fukutomi T. Favorable outcome in patients with breast cancer in the presence of pathological response after neoadjuvant endocrine therapy. Breast. 2007;16(5):482–8.

    PubMed  Google Scholar 

  142. Miller WR, Larionov AA, Renshaw L, Anderson TJ, White S, Murray J, Murray E, Hampton G, Walker JR, Ho S, Krause A, Evans DB, Dixon JM. Changes in breast cancer transcriptional profiles after treatment with the aromatase inhibitor, letrozole. Pharmacogenet Genomics. 2007;17(10):813–26.

    CAS  PubMed  Google Scholar 

  143. Gao Q, Patani N, Dunbier AK, Ghazoui Z, Zvelebil M, Martin LA, Dowsett M. Effect of aromatase inhibition on functional gene modules in estrogen receptor-positive breast cancer and their relationship with antiproliferative response. Clin Cancer Res. 2014;20(9):2485–94.

    CAS  PubMed  Google Scholar 

  144. Miller WR, Larionov A, Anderson TJ, Walker JR, Krause A, Evans DB, Dixon JM. Predicting response and resistance to endocrine therapy: profiling patients on aromatase inhibitors. Cancer. 2008;112(3 Suppl):689–94.

    CAS  PubMed  Google Scholar 

  145. Turnbull A, Arthur L, Renshaw L, Larionov A, Kay C, Dunbier A, et al. Accurate prediction and validation of response to endocrine therapy in breast cancer. J Clin Oncol (2015, in press)

    Google Scholar 

  146. Dunbier AK, Ghazoui Z, Anderson H, Salter J, Nerurkar A, Osin P, A’Hern R, Miller WR, Smith IE, Dowsett M. Molecular profiling of aromatase inhibitor-treated postmenopausal breast tumors identifies immune-related correlates of resistance. Clin Cancer Res. 2013;19(10):2775–86.

    CAS  PubMed  Google Scholar 

  147. Cheng J, Lei L, Xu J, Sun Y, Zhang Y, Wang X, Pan L, Shao Z, Zhang Y, Liu G. 18F-fluoromisonidazole PET/CT: a potential tool for predicting primary endocrine therapy resistance in breast cancer. J Nucl Med. 2013;54(3):333–40.

    CAS  PubMed  Google Scholar 

  148. Tilghman SL, Townley I, Zhong Q, Carriere PP, Zou J, Llopis SD, Preyan LC, Williams CC, Skripnikova E, Bratton MR, Zhang Q, Wang G. Proteomic signatures of acquired letrozole resistance in breast cancer: suppressed estrogen signaling and increased cell motility and invasiveness. Mol Cell Proteomics. 2013;12(9):2440–55.

    PubMed Central  CAS  PubMed  Google Scholar 

  149. Sun D, Chen G, Dellinger RW, Sharma AK, Lazarus P. Characterization of 17-dihydroexemestane glucuronidation: potential role of the UGT2B17 deletion in exemestane pharmacogenetics. Pharmacogenet Genomics. 2010;20(10):575–85.

    PubMed Central  CAS  PubMed  Google Scholar 

  150. Desta Z, Kreutz Y, Nguyen AT, Li L, Skaar T, Kamdem LK, Henry NL, Hayes DF, Storniolo AM, Stearns V, Hoffmann E, Tyndale RF, Flockhart DA. Plasma letrozole concentrations in postmenopausal women with breast cancer are associated with CYP2A6 genetic variants, body mass index, and age. Clin Pharmacol Ther. 2011;90(5):693–700.

    PubMed Central  CAS  PubMed  Google Scholar 

  151. Wang L, Ellsworth KA, Moon I, Pelleymounter LL, Eckloff BW, Martin YN, Fridley BL, Jenkins GD, Batzler A, Suman VJ, Ravi S, Dixon JM, Miller WR, Wieben ED, Buzdar A, Weinshilboum RM, Ingle JN. Functional genetic polymorphisms in the aromatase gene CYP19 vary the response of breast cancer patients to neoadjuvant therapy with aromatase inhibitors. Cancer Res. 2010;70(1):319–28.

    PubMed Central  CAS  PubMed  Google Scholar 

  152. Colomer R, Monzo M, Tusquets I, Rifa J, Baena JM, Barnadas A, Calvo L, Carabantes F, Crespo C, Munoz M, Llombart A, Plazaola A, Artells R, Gilabert M, Lloveras B, Alba E. A single-nucleotide polymorphism in the aromatase gene is associated with the efficacy of the aromatase inhibitor letrozole in advanced breast carcinoma. Clin Cancer Res. 2008;14(3):811–6.

    CAS  PubMed  Google Scholar 

  153. Zins K, Mogg M, Schneeberger C, Abraham D, Schreiber M. Analysis of the rs10046 polymorphism of aromatase (CYP19) in premenopausal onset of human breast cancer. Int J Mol Sci. 2014;15(1):712–24.

    PubMed Central  PubMed  Google Scholar 

  154. Miron L, Negura L, Peptanariu D, Marinca M. Research on aromatase gene (CYP19A1) polymorphisms as a predictor of endocrine therapy effectiveness in breast cancer. Rev Med Chir Soc Med Nat Iasi. 2012;116(4):997–1004.

    CAS  PubMed  Google Scholar 

  155. Sebastian S, Bulun SE. A highly complex organization of the regulatory region of the human CYP19 (aromatase) gene revealed by the human genome project. J Clin Endocrinol Metab. 2001;86(10):4600–2.

    CAS  PubMed  Google Scholar 

  156. Ma CX, Adjei AA, Salavaggione OE, Coronel J, Pelleymounter L, Wang L, Eckloff BW, Schaid D, Wieben ED, Adjei AA, Weinshilboum RM. Human aromatase: gene resequencing and functional genomics. Cancer Res. 2005;65(23):11071–82.

    CAS  PubMed  Google Scholar 

  157. Dunning AM, Dowsett M, Healey CS, Tee L, Luben RN, Folkerd E, Novik KL, Kelemen L, Ogata S, Pharoah PD, Easton DF, Day NE, Ponder BA. Polymorphisms associated with circulating sex hormone levels in postmenopausal women. J Natl Cancer Inst. 2004;96(12):936–45.

    CAS  PubMed  Google Scholar 

  158. Sowers MR, Wilson AL, Kardia SR, Chu J, Ferrell R. Aromatase gene (CYP 19) polymorphisms and endogenous androgen concentrations in a multiracial/multiethnic, multisite study of women at midlife. Am J Med. 2006;119(9 Suppl 1):S23–30.

    CAS  PubMed  Google Scholar 

  159. Baxter SW, Choong DY, Eccles DM, Campbell IG. Polymorphic variation in CYP19 and the risk of breast cancer. Carcinogenesis. 2001;22(2):347–9.

    CAS  PubMed  Google Scholar 

  160. Long JR, Kataoka N, Shu XO, Wen W, Gao YT, Cai Q, Zheng W. Genetic polymorphisms of the CYP19A1 gene and breast cancer survival. Cancer Epidemiol Biomarkers Prev. 2006;15(11):2115–22.

    CAS  PubMed  Google Scholar 

  161. Napoli N, Rastelli A, Ma C, Yarramaneni J, Vattikutti S, Moskowitz G, Giri T, Mueller C, Kulkarny V, Qualls C, Ellis M, Armamento-Villareal R. Genetic polymorphism at Val80 (rs700518) of the CYP19A1 gene is associated with aromatase inhibitor associated bone loss in women with ER+ breast cancer. Bone. 2013;55(2):309–14.

    PubMed Central  CAS  PubMed  Google Scholar 

  162. Fontein DB, Houtsma D, Nortier JW, Baak-Pablo RF, Kranenbarg EM, van der Straaten TR, Putter H, Seynaeve C, Gelderblom H, van de Velde CJ, Guchelaar HJ. Germline variants in the CYP19A1 gene are related to specific adverse events in aromatase inhibitor users: a substudy of Dutch patients in the TEAM trial. Breast Cancer Res Treat. 2014;144(3):599–606.

    CAS  PubMed  Google Scholar 

  163. Lazarus P, Sun D. Potential role of UGT pharmacogenetics in cancer treatment and prevention: focus on tamoxifen and aromatase inhibitors. Drug Metab Rev. 2010;42(1):182–94.

    PubMed Central  CAS  PubMed  Google Scholar 

  164. Folkerd EJ, Dixon JM, Renshaw L, A’Hern RP, Dowsett M. Suppression of plasma estrogen levels by letrozole and anastrozole is related to body mass index in patients with breast cancer. J Clin Oncol. 2012;30(24):2977–80.

    CAS  PubMed  Google Scholar 

  165. Miller WR, Dixon JM, Cameron DA, Anderson TJ. Biological and clinical effects of aromatase inhibitors in neoadjuvant therapy. J Steroid Biochem Mol Biol. 2001;79(1–5):103–7.

    CAS  PubMed  Google Scholar 

  166. Precht JC, Ganchev B, Heinkele G, Brauch H, Schwab M, Murdter TE. Simultaneous quantitative analysis of letrozole, its carbinol metabolite, and carbinol glucuronide in human plasma by LC-MS/MS. Anal Bioanal Chem. 2012;403(1):301–8.

    CAS  PubMed  Google Scholar 

  167. Santarpia L, Iwamoto T, Di Leo A, Hayashi N, Bottai G, Stampfer M, Andre F, Turner NC, Symmans WF, Hortobagyi GN, Pusztai L, Bianchini G. DNA repair gene patterns as prognostic and predictive factors in molecular breast cancer subtypes. Oncologist. 2013;18(10):1063–73.

    PubMed Central  CAS  PubMed  Google Scholar 

  168. Loi S, Haibe-Kains B, Majjaj S, Lallemand F, Durbecq V, Larsimont D, Gonzalez-Angulo AM, Pusztai L, Symmans WF, Bardelli A, Ellis P, Tutt AN, Gillett CE, Hennessy BT, Mills GB, Phillips WA, Piccart MJ, Speed TP, McArthur GA, Sotiriou C. PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer. Proc Natl Acad Sci USA. 2010;107(22):10208–13.

    PubMed Central  CAS  PubMed  Google Scholar 

  169. Bild AH, Yao G, Chang JT, Wang Q, Potti A, Chasse D, Joshi MB, Harpole D, Lancaster JM, Berchuck A, Jr Olson JA, Marks JR, Dressman HK, West M, Nevins JR. Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature. 2006;439(7074):353–7.

    CAS  PubMed  Google Scholar 

  170. Mefford D, Mefford J. Stromal genes add prognostic information to proliferation and histoclinical markers: a basis for the next generation of breast cancer gene signatures. PLoS ONE. 2012;7(6):e37646.

    PubMed Central  CAS  PubMed  Google Scholar 

  171. Larionov A. Classification of endocrine resistant breast cancers from transcriptomic datasets using multi-gene signatures in Cranfield Health, Applied Bioinformatics 2012, Cranfield University, UK: Cranfield Library and Information Service. p. 116.

    Google Scholar 

  172. Toy W, Shen Y, Won H, Green B, Sakr RA, Will M, Li Z, Gala K, Fanning S, King TA, Hudis C, Chen D, Taran T, Hortobagyi G, Greene G, Berger M, Baselga J, Chandarlapaty S. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet. 2013;45(12):1439–45.

    PubMed Central  CAS  PubMed  Google Scholar 

  173. Robinson DR, Wu YM, Vats P, Su F, Lonigro RJ, Cao X, Kalyana-Sundaram S, Wang R, Ning Y, Hodges L, Gursky A, Siddiqui J, Tomlins SA, Roychowdhury S, Pienta KJ, Kim SY, Roberts JS, Rae JM, Van Poznak CH, Hayes DF, Chugh R, Kunju LP, Talpaz M, Schott AF, Chinnaiyan AM. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet. 2013;45(12):1446–51.

    PubMed Central  CAS  PubMed  Google Scholar 

  174. Herynk MH, Fuqua SA. Estrogen receptor mutations in human disease. Endocr Rev. 2004;25(6):869–98.

    CAS  PubMed  Google Scholar 

  175. Zhang QX, Borg A, Wolf DM, Oesterreich S, Fuqua SA. An estrogen receptor mutant with strong hormone-independent activity from a metastatic breast cancer. Cancer Res. 1997;57(7):1244–9.

    CAS  PubMed  Google Scholar 

  176. Ellis MJ, Ding L, Shen D, Luo J, Suman VJ, Wallis JW, Van Tine BA, Hoog J, Goiffon RJ, Goldstein TC, Ng S, Lin L, Crowder R, Snider J, Ballman K, Weber J, Chen K, Koboldt DC, Kandoth C, Schierding WS, McMichael JF, Miller CA, Lu C, Harris CC, McLellan MD, Wendl MC, DeSchryver K, Allred DC, Esserman L, Unzeitig G, Margenthaler J, Babiera GV, Marcom PK, Guenther JM, Leitch M, Hunt K, Olson J, Tao Y, Maher CA, Fulton LL, Fulton RS, Harrison M, Oberkfell B, Du F, Demeter R, Vickery TL, Elhammali A, Piwnica-Worms H, McDonald S, Watson M, Dooling DJ, Ota D, Chang LW, Bose R, Ley TJ, Piwnica-Worms D, Stuart JM, Wilson RK, Mardis ER. Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature. 2012;486(7403):353–60.

    PubMed Central  CAS  PubMed  Google Scholar 

  177. Ma CX, Ellis MJ. The cancer genome atlas: clinical applications for breast cancer. Oncology (Williston Park). 2013;27(12):1263–1269, 1274–1269.

    Google Scholar 

  178. Ellis MJ, Perou CM. The genomic landscape of breast cancer as a therapeutic roadmap. Cancer Discov. 2013;3(1):27–34.

    PubMed Central  CAS  PubMed  Google Scholar 

  179. Baselga J, Semiglazov V, van Dam P, Manikhas A, Bellet M, Mayordomo J, Campone M, Kubista E, Greil R, Bianchi G, Steinseifer J, Molloy B, Tokaji E, Gardner H, Phillips P, Stumm M, Lane HA, Dixon JM, Jonat W, Rugo HS. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol. 2009;27(16):2630–7.

    CAS  PubMed  Google Scholar 

  180. Lopez-Knowles E, Segal CV, Gao Q, Garcia-Murillas I, Turner NC, Smith I, Martin LA, Dowsett M. Relationship of PIK3CA mutation and pathway activity with anti-proliferative response to aromatase inhibition. Breast Cancer Res. 2014;16(3):R68.

    PubMed Central  PubMed  Google Scholar 

  181. Miller WR, Larionov AA. Understanding the mechanisms of aromatase inhibitor resistance. Breast Cancer Res. 2012;14(1):201.

    PubMed Central  CAS  PubMed  Google Scholar 

  182. Turnbull AK, Kitchen RR, Larionov AA, Renshaw L, Dixon JM, Sims AH. Direct integration of intensity-level data from Affymetrix and Illumina microarrays improves statistical power for robust reanalysis. BMC Med Genomics. 2012;5:35.

    PubMed Central  PubMed  Google Scholar 

Download references

Conflicts of Interest

No potential conflicts of interest were disclosed.

Author information

Authors and Affiliations

  1. Academic Laboratory of Medical Genetics, School of Clinical Medicine, University of Cambridge, Cambridge, UK

    Alexey A. Larionov

  2. Statistics and Computational Biology Laboratory, Cancer Research UK Cambridge Institute, Cambridge, UK

    Alexey A. Larionov

  3. University of Edinburgh, Flat 5A 18 Hopetoun Road, South Queensferry, Edinburgh, EH30 9 RA, UK

    William R. Miller

Authors
  1. Alexey A. Larionov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William R. Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to William R. Miller .

Editor information

Editors and Affiliations

  1. Academic Laboratory of Medical Genetics, School of Clinical Medicine, Cancer Research UK Cambridge Institute, Statistics and Computational Biology Laboratory & University of Cambridge, Cambridge, United Kingdom

    Alexey Larionov

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Larionov, A.A., Miller, W.R. (2015). Prediction of Response to Aromatase Inhibitors in Breast Cancer. In: Larionov, A. (eds) Resistance to Aromatase Inhibitors in Breast Cancer. Resistance to Targeted Anti-Cancer Therapeutics, vol 8. Springer, Cham. https://doi.org/10.1007/978-3-319-17972-8_10

Download citation

Publish with us

Policies and ethics

Search

Navigation