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  • Review Article
  • Published:

Luminal breast cancer: from biology to treatment

Nature Reviews Clinical Oncology volume 10, pages 494–506 (2013)Cite this article

Subjects

Key Points

  • Results from trials using gene-expression assays will better define the women with oestrogen receptor-positive breast cancer and 0–3 positive axillary lymph nodes who do not need adjuvant chemotherapy

  • Extended adjuvant hormone therapy might be an important strategy to target tumour dormancy in luminal tumours

  • The intriguing hypothesis that bisphosphonates might decrease recurrence in women with a low-oestrogen environment is supported by subgroup analyses from several prospective trials

  • Detecting and targeting minimal residual disease is currently being explored as a way to improve outcome for women with these tumours

  • Targeting the PI3K/AKT/mTOR pathway is one of the most-promising approaches to reversing endocrine resistance; the intertumour and intratumour heterogeneity of luminal breast cancer has implications for designing new therapies

  • The challenge will be to identify and target epistatic gene interactions in luminal tumours and to tailor therapy based on tumour evolution in space and time

Abstract

Oestrogen receptor (ER)-positive—or luminal—tumours represent around two-thirds of all breast cancers. Luminal breast cancer is a highly heterogeneous disease comprising different histologies, gene-expression profiles and mutational patterns, with very varied clinical courses and responses to systemic treatment. Despite adjuvant endocrine therapy and chemotherapy treatment for patients at high risk of relapse, both early and late relapses still occur, a fact that highlights the unmet medical needs of these patients. Ongoing research aims to identify those patients who can be spared adjuvant chemotherapy and who will benefit from extended adjuvant hormone therapy. This research also aims to explore the role of adjuvant bisphosphonates, to interrogate new agents for targeting minimal residual disease, and to address endocrine resistance. Data from next-generation sequencing studies have given us new insight into the biology of luminal breast cancer and, together with advances in preclinical models and the availability of newer targeted agents, have led to the testing of rationally chosen combination treatments in clinical trials. However, a major challenge will be to make sense of the large amount of patient genomic data that is becoming increasingly available. This analysis will be critical to our understanding how intertumour and intratumour heterogeneity can influence treatment response and resistance.

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Figure 1: Research questions and respective ongoing studies in patients with oestrogen receptor-positive early stage breast cancer.
Figure 2: Vicious cycle of occult tumour cells and osteoclasts in breast cancer.77,78,79
Figure 3: Genomic and epigenomic landscape, pathways and drugs to reverse endocrine resistance in oestrogen receptor-positive breast cancer.

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References

  1. Malvezzi, M., Bertuccio, P., Levi, F., La Vecchia, C. & Negri, E. European cancer mortality predictions for the year 2013. Ann. Oncol. 24, 792–800 (2013).

    Article  CAS  PubMed  Google Scholar 

  2. Goldhirsch, A. et al. 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. 22, 1736–1747 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Colleoni, M. et al. Outcome of special types of luminal breast cancer. Ann. Oncol. 23, 1428–1436 (2012).

    Article  CAS  PubMed  Google Scholar 

  4. Perou, C. M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Sørlie, T. et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc. Natl Acad. Sci. USA 98, 10869–10874 (2001).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Sotiriou, C. et al. Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc. Natl Acad. Sci. USA 100, 10393–10398 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Creighton, C. J. The molecular profile of luminal B breast cancer. Biologics 6, 289–297 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Sotiriou, C. & Pusztai, L. Gene-expression signatures in breast cancer. N. Engl. J. Med. 360, 790–800 (2009).

    Article  CAS  PubMed  Google Scholar 

  9. Ignatiadis, M. et al. Gene modules and response to neoadjuvant chemotherapy in breast cancer subtypes: a pooled analysis. J. Clin. Oncol. 30, 1996–2004 (2012).

    Article  CAS  PubMed  Google Scholar 

  10. Rouzier, R. et al. Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin. Cancer Res. 11, 5678–5685 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Sorlie, T. et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc. Natl Acad. Sci. USA 100, 8418–8423 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hu, Z. et al. The molecular portraits of breast tumors are conserved across microarray platforms. BMC Genomics 7, 96 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Parker, J. S. et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J. Clin. Oncol. 27, 1160–1167 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Desmedt, C. et al. Biological processes associated with breast cancer clinical outcome depend on the molecular subtypes. Clin. Cancer Res. 14, 5158–5165 (2008).

    Article  CAS  PubMed  Google Scholar 

  15. Wirapati, P. et al. Meta-analysis of gene expression profiles in breast cancer: toward a unified understanding of breast cancer subtyping and prognosis signatures. Breast Cancer Res. 10, R65 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Haibe-Kains, B. et al. A three-gene model to robustly identify breast cancer molecular subtypes. J. Natl Cancer Inst. 104, 311–325 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Weigelt, B. et al. Breast cancer molecular profiling with single sample predictors: a retrospective analysis. Lancet Oncol. 11, 339–349 (2010).

    Article  CAS  PubMed  Google Scholar 

  18. Paik, S. et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N. Engl. J. Med. 351, 2817–2826 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. van't Veer, L. J. et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 415, 530–536 (2002).

    Article  CAS  Google Scholar 

  20. Fan, C. et al. Concordance among gene-expression-based predictors for breast cancer. N. Engl. J. Med. 355, 560–569 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. Teutsch, S. M. et al. The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) initiative: methods of the EGAPP Working Group. Genet. Med. 11, 3–14 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Simon, R. M., Paik, S. & Hayes, D. F. Use of archived specimens in evaluation of prognostic and predictive biomarkers. J. Natl Cancer Inst. 101, 1446–1452 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Azim, H. A. Jr et al. Utility of prognostic genomic tests in breast cancer practice: The IMPAKT 2012 Working Group Consensus Statement. Ann. Oncol. 24, 647–654 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  24. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  25. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  26. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  27. Dowsett, M. et al. Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group. J. Natl Cancer Inst. 103, 1656–1664 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nielsen, T. O. et al. An international Ki67 reproducibility study [abstract]. Cancer Res. 72 (Suppl. 3), S4–S6 (2012).

    Google Scholar 

  29. Curtis, C. et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486, 346–352 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Stephens, P. J. et al. The landscape of cancer genes and mutational processes in breast cancer. Nature 486, 400–404 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Nik-Zainal, S. et al. Mutational processes molding the genomes of 21 breast cancers. Cell 149, 979–993 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Nik-Zainal, S. et al. The life history of 21 breast cancers. Cell 149, 994–1007 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012).

  34. Banerji, S. et al. Sequence analysis of mutations and translocations across breast cancer subtypes. Nature 486, 405–409 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ellis, M. J. et al. Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature 486, 353–360 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ellis, M. J. & Perou, C. M. The genomic landscape of breast cancer as a therapeutic roadmap. Cancer Discov. 3, 27–34 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Peto, R. et al. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet 379, 432–444 (2012).

    Article  CAS  PubMed  Google Scholar 

  38. Sotiriou, C. et al. Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis. J. Natl Cancer Inst. 98, 262–272 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Gnant, M. et al. Clinical validation of the PAM50 risk of recurrence (ROR) score for predicting residual risk of distant-recurrence (DR) after endocrine therapy in postmenopausal women with ER+ early breast cancer (EBC): An ABCSG study [abstract]. Cancer Res. 72 (Suppl. 3), P2-10-02 (2012).

    Google Scholar 

  40. Ma, X. J. et al. A five-gene molecular grade index and HOXB13:IL17BR are complementary prognostic factors in early stage breast cancer. Clin. Cancer Res. 14, 2601–2608 (2008).

    Article  CAS  PubMed  Google Scholar 

  41. Filipits, M. et al. 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. 17, 6012–6020 (2011).

    Article  CAS  PubMed  Google Scholar 

  42. Dubsky, P. et al. EndoPredict improves the prognostic classification derived from common clinical guidelines in ER-positive, HER2-negative early breast cancer. Ann. Oncol. 24, 640–647 (2013).

    Article  CAS  PubMed  Google Scholar 

  43. Dowsett, M. et al. Prediction of risk of distant recurrence using the 21-gene recurrence score in node-negative and node-positive postmenopausal patients with breast cancer treated with anastrozole or tamoxifen: a TransATAC study. J. Clin. Oncol. 28, 1829–1834 (2010).

    Article  PubMed  Google Scholar 

  44. Rutgers, E. et al. The EORTC 10041/BIG 03–04 MINDACT trial is feasible: results of the pilot phase. Eur. J. Cancer 47, 2742–2749 (2011).

    Article  PubMed  Google Scholar 

  45. Ravdin, P. M. et al. Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer. J. Clin. Oncol. 19, 980–991 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Paik, S. et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J. Clin. Oncol. 24, 3726–3734 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Albain, K. S. et al. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol. 11, 55–65 (2010).

    Article  CAS  PubMed  Google Scholar 

  48. Small, G. W., Shi, Y. Y., Higgins, L. S. & Orlowski, R. Z. Mitogen-activated protein kinase phosphatase-1 is a mediator of breast cancer chemoresistance. Cancer Res. 67, 4459–4466 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Davies, C. et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 378, 771–784 (2011).

    Article  CAS  PubMed  Google Scholar 

  50. Dowsett, M. et al. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J. Clin. Oncol. 28, 509–518 (2010).

    Article  CAS  PubMed  Google Scholar 

  51. Goss, P. E. et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N. Engl. J. Med. 349, 1793–1802 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Jakesz, R. et al. Extended adjuvant therapy with anastrozole among postmenopausal breast cancer patients: results from the randomized Austrian Breast and Colorectal Cancer Study Group Trial 6a. J. Natl Cancer Inst. 99, 1845–1853 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. Mamounas, E. P. et al. Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast and Bowel Project B-33 trial. J. Clin. Oncol. 26, 1965–1971 (2008).

    Article  CAS  PubMed  Google Scholar 

  54. Goss, P. E. et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J. Natl Cancer Inst. 97, 1262–1271 (2005).

    Article  CAS  PubMed  Google Scholar 

  55. US National Library of Medicine. ClinicalTrials.gov [online], (2010).

  56. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  57. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  58. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  59. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  60. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  61. Goss, P. E. & Chambers, A. F. Does tumour dormancy offer a therapeutic target? Nat. Rev. Cancer 10, 871–877 (2010).

    Article  CAS  PubMed  Google Scholar 

  62. Davies, C. et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 381, 805–816 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Fisher, B., Dignam, J., Bryant, J. & Wolmark, N. Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J. Natl Cancer Inst. 93, 684–690 (2001).

    Article  CAS  PubMed  Google Scholar 

  64. Stewart, H. J. et al. Randomised comparison of 5 years of adjuvant tamoxifen with continuous therapy for operable breast cancer. The Scottish Cancer Trials Breast Group. Br. J. Cancer 74, 297–299 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Tormey, D. C., Gray, R. & Falkson, H. C. Postchemotherapy adjuvant tamoxifen therapy beyond five years in patients with lymph node-positive breast cancer. Eastern Cooperative Oncology Group. J. Natl Cancer Inst. 88, 1828–1833 (1996).

    Article  CAS  PubMed  Google Scholar 

  66. US National Library of Medicine. ClinicalTrials.gov [online], (2007).

  67. Kennecke, H. F. et al. Late risk of relapse and mortality among postmenopausal women with estrogen responsive early breast cancer after 5 years of tamoxifen. Ann. Oncol. 18, 45–51 (2007).

    Article  CAS  PubMed  Google Scholar 

  68. Goss, P. E. et al. Impact of premenopausal status at breast cancer diagnosis in women entered on the placebo-controlled NCIC CTG MA17 trial of extended adjuvant letrozole. Ann. Oncol. 24, 355–361 (2013).

    Article  CAS  PubMed  Google Scholar 

  69. Goss, P. E. et al. Efficacy of letrozole extended adjuvant therapy according to estrogen receptor and progesterone receptor status of the primary tumor: National Cancer Institute of Canada Clinical Trials Group MA.17. J. Clin. Oncol. 25, 2006–2011 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. Sgroi, D. C. et al. Comparative performance of Breast Cancer Index (BCI) vs. Oncotype DX and IHC4 in the prediction of late recurrence in hormonal receptor-positive lymph node-negative breast cancer patients: a TransATAC Study [abstract]. Cancer Res. 72 (Suppl. 3), S1–S9 (2012).

    Google Scholar 

  71. Dubsky, P. et al. The EndoPredict score identifies late distant metastases in ER+/HER2– breast cancer patients [abstract]. Cancer Res. 72 (Suppl. 3), S4–S3 (2012).

    Google Scholar 

  72. Gnant, M. et al. Predicting risk for late metastasis: The PAM50 risk of recurrence (ROR) score after 5 years of endocrine therapy in postmenopausal women with HR+ early breast cancer: A study on 1,478 patients from the ABCSG-8 trial [abstract]. Ann. Oncol. 24 (Suppl. 3), 53O_PR (2013).

    Google Scholar 

  73. Sestak, I. et al. Comparison of five different scores for the prediction of late recurrence for oestrogen receptor positive breast cancer [abstract]. Ann. Oncol. 24 (Suppl. 3), 54O_PR (2013).

    Google Scholar 

  74. Aguirre-Ghiso, J. A. Models, mechanisms and clinical evidence for cancer dormancy. Nat. Rev. Cancer 7, 834–846 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Bragado, P., Sosa, M. S., Keely, P., Condeelis, J. & Aguirre-Ghiso, J. A. Microenvironments dictating tumor cell dormancy. Recent Results Cancer Res. 195, 25–39 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Uhr, J. W. & Pantel, K. Controversies in clinical cancer dormancy. Proc. Natl Acad. Sci. USA 108, 12396–12400 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Roodman, G. D. Mechanisms of bone metastasis. N. Engl. J. Med. 350, 1655–1664 (2004).

    Article  CAS  PubMed  Google Scholar 

  78. Akhtari, M., Mansuri, J., Newman, K. A., Guise, T. M. & Seth, P. Biology of breast cancer bone metastasis. Cancer Biol. Ther. 7, 3–9 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Coleman, R., Gnant, M., Morgan, G. & Clezardin, P. Effects of bone-targeted agents on cancer progression and mortality. J. Natl Cancer Inst. 104, 1059–1067 (2012).

    Article  CAS  PubMed  Google Scholar 

  80. Aft, R. et al. Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: an open label, randomised, phase 2 trial. Lancet Oncol. 11, 421–428 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Solomayer, E. F. et al. Influence of zoledronic acid on disseminated tumor cells in primary breast cancer patients. Ann. Oncol. 23, 2271–2277 (2012).

    Article  PubMed  Google Scholar 

  82. Coleman, R. E. et al. Breast-cancer adjuvant therapy with zoledronic acid. N. Engl. J. Med. 365, 1396–1405 (2011).

    Article  CAS  PubMed  Google Scholar 

  83. Gnant, M. et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N. Engl. J. Med. 360, 679–691 (2009).

    Article  CAS  PubMed  Google Scholar 

  84. Gnant, M. et al. Long-term follow-up in ABCSG-12: significantly improved overall survival with adjuvant zoledronic acid in premenopausal patients with endocrine-receptor-positive early breast cancer [abstract]. Cancer Res. 24 (Suppl. 3), S1–S2 (2011).

    Google Scholar 

  85. Coleman, R. et al. Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): final 60-month results. Ann. Oncol. 24, 398–405 (2013).

    Article  CAS  PubMed  Google Scholar 

  86. Paterson, A. H. et al. Oral clodronate for adjuvant treatment of operable breast cancer (National Surgical Adjuvant Breast and Bowel Project protocol B-34): a multicentre, placebo-controlled, randomised trial. Lancet Oncol. 13, 734–742 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  88. Dubsky, P. & Bartsch, R. Bisphosphonates in early breast cancer. Lancet Oncol. 13, 660–661 (2012).

    Article  PubMed  Google Scholar 

  89. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  90. Pantel, K., Brakenhoff, R. H. & Brandt, B. Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nat. Rev. Cancer 8, 329–340 (2008).

    Article  CAS  PubMed  Google Scholar 

  91. Ignatiadis, M. & Piccart, M. Liquid biopsy to test new treatment strategies in breast cancer: are we there yet? Ann. Oncol. 23, 1653–1655 (2012).

    Article  CAS  PubMed  Google Scholar 

  92. Lianidou, E. S. Circulating tumor cells—new challenges ahead. Clin. Chem. 58, 805–807 (2012).

    Article  CAS  PubMed  Google Scholar 

  93. Bidard, F. C. et al. Single circulating tumor cell detection and overall survival in nonmetastatic breast cancer. Ann. Oncol. 21, 729–733 (2010).

    Article  PubMed  Google Scholar 

  94. Lucci, A. et al. Circulating tumour cells in non-metastatic breast cancer: a prospective study. Lancet Oncol. 13, 688–695 (2012).

    Article  PubMed  Google Scholar 

  95. Rack, B., Andergassen, U., Janni, W. & Neugebauer, J. CTCs in primary breast cancer (I). Recent Results Cancer Res. 195, 179–185 (2012).

    Article  PubMed  Google Scholar 

  96. Paik, S. Kim, C. & Wolmark, N. HER2 status and benefit from adjuvant trastuzumab in breast cancer. N. Engl. J. Med. 358, 1409–1411 (2008).

    Article  CAS  PubMed  Google Scholar 

  97. Bozionellou, V. et al. Trastuzumab administration can effectively target chemotherapy-resistant cytokeratin-19 messenger RNA-positive tumor cells in the peripheral blood and bone marrow of patients with breast cancer. Clin. Cancer Res. 10, 8185–8194 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. Georgoulias, V. et al. Trastuzumab decreases the incidence of clinical relapses in patients with early breast cancer presenting chemotherapy-resistant CK19 mRNA-positive circulating tumor cells: results of a randomized phase II study. Ann. Oncol. 23, 1744–1750 (2012).

    Article  CAS  PubMed  Google Scholar 

  99. Ithimakin, S. et al. HER2 drives luminal breast cancer stem cells in the absence of HER2 amplification: implications for efficacy of adjuvant trastuzumab. Cancer Res. 73, 1635–1646 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  101. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  102. Di Leo, A. et al. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with oestrogen receptor-positive advanced breast cancer. J. Clin. Oncol. 28, 4594–4600 (2010).

    Article  CAS  PubMed  Google Scholar 

  103. Mehta, R. S. et al. Combination anastrozole and fulvestrant in metastatic breast cancer. N. Engl. J. Med. 367, 435–444 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Bergh, J. et al. FACT: an open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-line therapy for patients with receptor-positive postmenopausal breast cancer. J. Clin. Oncol. 30, 1919–1925 (2012).

    Article  CAS  PubMed  Google Scholar 

  105. Johnston, S. et al. Fulvestrant alone or with concomitant anastrozole vs exemestane following progression on non-steroidal aromatase inhibitor—first results of the SoFEa trial (CRUKE/03/021 & CRUK/09/007) (ISRCTN44195747) [abstract]. Eur. J. Cancer 48 (Suppl. 3), 2LBA (2012).

    Article  Google Scholar 

  106. Baum, M. et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 359, 2131–2139 (2002).

    Article  CAS  PubMed  Google Scholar 

  107. Schiff, R. et al. Cross-talk between estrogen receptor and growth factor pathways as a molecular target for overcoming endocrine resistance. Clin. Cancer Res. 10 (1 Pt 2), 331S–336S (2004).

    Article  CAS  PubMed  Google Scholar 

  108. Johnston, S. et al. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J. Clin. Oncol. 27, 5538–5546 (2009).

    Article  CAS  PubMed  Google Scholar 

  109. Kaufman, B. et al. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J. Clin. Oncol. 27, 5529–5537 (2009).

    Article  CAS  PubMed  Google Scholar 

  110. Zoncu, R., Efeyan, A. & Sabatini, D. M. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat. Rev. Mol. Cell. Biol. 12, 21–35 (2011).

    Article  CAS  PubMed  Google Scholar 

  111. Sabine, V. S. et al. PIK3CA mutations are linked to PgR expression: a Tamoxifen Exemestane Adjuvant Multinational (TEAM) pathology study [abstract]. Cancer Res. 72 (Suppl. 3), S1–S5 (2012).

    Google Scholar 

  112. Crowder, R. J. et al. PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer. Cancer Res. 69, 3955–3962 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Stemke-Hale, K. et al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res. 68, 6084–6091 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Loi, S. et al. PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer. Proc. Natl Acad. Sci. USA 107, 10208–10213 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Rodon, J., Dienstmann, R., Serra, V. & Tabernero, J. Development of PI3K inhibitors: lessons learned from early clinical trials. Nat. Rev. Clin. Oncol. 10, 143–153 (2013).

    Article  CAS  PubMed  Google Scholar 

  116. Zardavas, D., Baselga, J. & Piccart, M. Emerging targeted agents in metastatic breast cancer. Nat. Rev. Clin. Oncol. 10, 191–210 (2013).

    Article  CAS  PubMed  Google Scholar 

  117. Baselga, J. et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 366, 520–529 (2012).

    Article  CAS  PubMed  Google Scholar 

  118. Bachelot, T. et al. 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, 2718–2724 (2012).

    Article  CAS  PubMed  Google Scholar 

  119. Wolff, A. C. et al. Randomized phase III placebo-controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer. J. Clin. Oncol. 31, 195–202 (2013).

    Article  CAS  PubMed  Google Scholar 

  120. Baselga, J. et al. 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. 27, 2630–2637 (2009).

    Article  CAS  PubMed  Google Scholar 

  121. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  122. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  123. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  124. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  125. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  126. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  127. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  128. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  129. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  130. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  131. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  132. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  133. Janku, F. et al. PIK3CA mutations in patients with advanced cancers treated with PI3K/AKT/mTOR axis inhibitors. Mol. Cancer Ther. 10, 558–565 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Oliveira, M. et al. PI3K pathway (PI3Kp) dysregulation and response to pan-PI3K/AKT/mTOR/dual PI3K-mTOR inhibitors (PI3Kpi) in metastatic breast cancer (MBC) patients (pts) [abstract]. J. Clin. Oncol. 30 (Suppl.), a509 (2012).

    Google Scholar 

  135. Iyer, G. et al. Genome sequencing identifies a basis for everolimus sensitivity. Science 338, 221 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Klümpen, H. J. et al. mTOR inhibitor treatment of pancreatic cancer in a patient with Peutz-Jeghers syndrome. J. Clin. Oncol. 29, e150–e153 (2011).

    Article  PubMed  Google Scholar 

  137. Loi, S. et al. PIK3CA genotype and a PIK3CA mutation-related gene signature and response to everolimus and letrozole in estrogen receptor positive breast cancer. PLoS ONE 8, e53292 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Bachelot, T. et al. Translational studies within the TAMRAD randomized Gineco trial: evidence for TORC1 activation marker as a predictive factor for everolimus efficacy in metastatic breast cancer [abstract]. Ann. Oncol. 23 (Suppl. 2), 13O_PR (2012).

    Google Scholar 

  139. Tabernero, J. et al. Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. J. Clin. Oncol. 26, 1603–1610 (2008).

    Article  CAS  PubMed  Google Scholar 

  140. Carracedo, A. et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J. Clin. Invest. 118, 3065–3074 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Di Cosimo, S. et al. A phase I study of the oral mTOR inhibitor ridaforolimus (RIDA) in combination with the IGF-1R antibody dalotozumab (DALO) in patients (pts) with advanced solid tumors [abstract]. J. Clin. Oncol. 28 (Suppl. 15), a3008 (2010).

    Article  Google Scholar 

  142. Vilar, E., Perez-Garcia, J. & Tabernero, J. Pushing the envelope in the mTOR pathway: the second generation of inhibitors. Mol. Cancer Ther. 10, 395–403 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Piccart, M. et al. Assessment of genetic alterations in postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer from the BOLERO-2 trial by next-generation sequencing [abstract]. Ann. Oncol. 24 (Suppl. 3), 420-PR (2013).

    Google Scholar 

  144. Rodon, J. et al. Towards defining the genetic framework for clinical response to treatment with BYL719, a PI3Kalpha-specific inhibitor [abstract]. Cancer Res. 72 (Suppl. 1), LB-65 (2013).

    Google Scholar 

  145. Weinberg, R. A. The retinoblastoma protein and cell cycle control. Cell 81, 323–330 (1995).

    Article  CAS  PubMed  Google Scholar 

  146. Harbour, J. W., Luo, R. X., Dei, S. A., Postigo, A. A. & Dean, D. C. Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell 98, 859–869 (1999).

    Article  CAS  PubMed  Google Scholar 

  147. Finn, R. S. et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 11, R77 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Finn, R. S. et al. Results of a randomized phase 2 study of PD 0332991, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2– advanced breast cancer (BC) [abstract]. Cancer Res. 72 (Suppl. 3), S1–S6 (2012).

    Google Scholar 

  149. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  150. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  151. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  152. Turner, N. & Grose, R. Fibroblast growth factor signalling: from development to cancer. Nat. Rev. Cancer 10, 116–129 (2010).

    Article  CAS  PubMed  Google Scholar 

  153. Dieci, M. V., Arnedos, M., Andre, F. & Soria, J. C. Fibroblast growth factor receptor inhibitors as a cancer treatment: from a biologic rationale to medical perspectives. Cancer Discov. 3, 264–279 (2013).

    Article  CAS  PubMed  Google Scholar 

  154. Elbauomy Elshaikh, S. et al. FGFR1 amplification in breast carcinomas: a chromogenic in situ hybridisation analysis. Breast Cancer Res. 9, R23 (2007).

    Article  CAS  Google Scholar 

  155. Turner, N. et al. FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res. 70, 2085–2094 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Andre, F. et al. A multicenter, open-label phase II trial of dovitinib, a fibroblast growth factor receptor 1 (FGFR1) inhibitor, in FGFR1-amplified and nonamplified metastatic breast cancer (BC) [abstract]. J. Clin. Oncol. 29 (Suppl. 27), a289 (2011).

    Article  Google Scholar 

  157. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  158. Dienstmann, R. et al. Significant antitumor activity of E-3810, a novel FGFR and VEGFR inhibitor, in patients with FGFR1 amplified breast cancer [abstract]. Ann. Oncol. 23 (Suppl. 9), a2115 (2012).

    Google Scholar 

  159. Yardley, D. A. et al. Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor. J. Clin. Oncol. 31, 2128–2135 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Piccart-Gebhart, M. J. et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N. Engl. J. Med. 353, 1659–1672 (2005).

    Article  CAS  PubMed  Google Scholar 

  161. Druker, B. J. et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N. Engl. J. Med. 344, 1031–1037 (2001).

    Article  CAS  PubMed  Google Scholar 

  162. Ashworth, A., Lord, C. J. & Reis-Filho, J. S. Genetic interactions in cancer progression and treatment. Cell 145, 30–38 (2011).

    Article  CAS  PubMed  Google Scholar 

  163. Yates, L. R. & Campbell, P. J. Evolution of the cancer genome. Nat. Rev. Genet. 13, 795–806 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Fong, P. C. et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123–134 (2009).

    Article  CAS  PubMed  Google Scholar 

  165. Berns, K. et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12, 395–402 (2007).

    Article  CAS  PubMed  Google Scholar 

  166. Baselga, J. et al. Biomarker analyses in CLEOPATRA: A phase III, placebo-controlled study of pertuzumab in HER2-positive, first-line metastatic breast cancer (MBC) [abstract]. Cancer Res. 72 (Suppl. 3), S5–S1 (2012).

    Google Scholar 

  167. Joensuu, H. et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N. Engl. J. Med. 354, 809–820 (2006).

    Article  CAS  PubMed  Google Scholar 

  168. Loi, S. et al. Somatic mutation profiling and associations with prognosis and trastuzumab benefit in early breast cancer. J. Natl Cancer Inst. 105, 960–967 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Courjal, F. et al. Mapping of DNA amplifications at 15 chromosomal localizations in 1875 breast tumors: definition of phenotypic groups. Cancer Res. 57, 4360–4367 (1997).

    CAS  PubMed  Google Scholar 

  170. Karlseder, J. et al. Patterns of DNA amplification at band q13 of chromosome 11 in human breast cancer. Genes Chromosomes Cancer 9, 42–48 (1994).

    Article  CAS  PubMed  Google Scholar 

  171. Ginestier, C. et al. Prognosis and gene expression profiling of 20q13-amplified breast cancers. Clin. Cancer Res. 12, 4533–4544 (2006).

    Article  CAS  PubMed  Google Scholar 

  172. Navin, N. E. Investigating breast cancer with single-cell sequencing [abstract]. Cancer Res. 72 (Suppl. 3), ES5–ES3 (2012).

    Google Scholar 

  173. Gong, Y., Booser, D. J. & Sneige, N. Comparison of HER-2 status determined by fluorescence in situ hybridization in primary and metastatic breast carcinoma. Cancer 103, 1763–1769 (2005).

    Article  CAS  PubMed  Google Scholar 

  174. Lindström, L. S. et al. Clinically used breast cancer markers such as estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 are unstable throughout tumor progression. J. Clin. Oncol. 30, 2601–2608 (2012).

    Article  PubMed  Google Scholar 

  175. Hoefnagel, L. D. et al. Receptor conversion in distant breast cancer metastases. Breast Cancer Res. 12, R75 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  176. Cardoso, F. et al. Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 22 (Suppl. 6), v25–v30 (2011).

    Google Scholar 

  177. Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Garraway, L. A. & Baselga, J. Whole-genome sequencing and cancer therapy: is too much ever enough? Cancer Discov. 2, 766–768 (2012).

    Article  PubMed  Google Scholar 

  179. Ignatiadis, M. & Reinholz, M. M. Minimal residual disease and circulating tumor cells in breast cancer. Breast Cancer Res. 13, 222 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Dawson, S. J. et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N. Engl. J. Med. 368, 1199–1209 (2013).

    Article  CAS  PubMed  Google Scholar 

  181. Murtaza, M. et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 497, 108–112 (2013).

    Article  CAS  PubMed  Google Scholar 

  182. de Vries, E. G., Oude Munnink, T. H., van Vugt, M. A. & Nagengast, W. B. Toward molecular imaging-driven drug development in oncology. Cancer Discov. 1, 25–28 (2011).

    Article  CAS  PubMed  Google Scholar 

  183. Beltran, H. et al. Targeted next-generation sequencing of advanced prostate cancer identifies potential therapeutic targets and disease heterogeneity. Eur. Urol. 63, 920–926 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Roychowdhury, S. et al. Personalized oncology through integrative high-throughput sequencing: a pilot study. Sci. Transl. Med. 3, 111ra121 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Rodón, J. et al. Molecular prescreening to select patient population in early clinical trials. Nat. Rev. Clin. Oncol. 9, 359–366 (2012).

    Article  CAS  PubMed  Google Scholar 

  186. Tentler, J. J. et al. Patient-derived tumour xenografts as models for oncology drug development. Nat. Rev. Clin. Oncol. 9, 338–350 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

M. Ignatiadis and C. Sotiriou received grants from the Breast Cancer Research Foundation (BCRF), “Fonds de la recherche scientifique” (FNRS), “Les Amis de Bordet,” and the MEDIC foundation.

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  1. Department of Medical Oncology and Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, 121 Boulevard de Waterloo, Brussels, 1000, Belgium

    Michail Ignatiadis & Christos Sotiriou

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  1. Michail Ignatiadis
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  2. Christos Sotiriou
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Both authors researched data for the article and made a substantial contribution to discussions of the content. M. Ignatiadis wrote the article and both authors edited the manuscript before submission.

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Correspondence to Christos Sotiriou.

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Competing interests

C. Sotiriou is co-inventor of a gene-expression grade index patent and co-inventor of a gene module PIK3CA patent. M. Ignatiadis declares no competing interests.

PowerPoint slides

Glossary

Driver mutations

Mutations observed in cancer genes that have an important role in oncogenesis or cancer progression by providing clonal advantage

Epistasis

When the effect of a mutation in one gene is modified by mutation(s) in one or several other genes

Exome sequencing

Sequencing of the coding regions (exons) of the genes in a genome

Oncogene addiction

The dependency of a tumour cell on the activity of an oncogene

Passenger mutations

Mutations that do not confer clonal advantage

Prognostic gene signature

Classifier assigning a breast cancer case into good or bad prognosis based on an algorithm that relies on the expression of a predefined gene set

Single-sample predictor

Classifier assigning a breast cancer case into a molecular subtype (basal-like, HER2-enriched, luminal A and luminal B) based on similarities in gene expression between this case and molecular subtype centroids

Subtype classification model

Classifier assigning a breast cancer case into a molecular subtype (basal-like, HER2-enriched, luminal A and luminal B) based on Gaussian distributions of gene expression of three gene sets associated with oestrogen receptor, HER2 and proliferation

Whole-genome sequencing

Sequencing of the coding and non-coding regions of the genome

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Ignatiadis, M., Sotiriou, C. Luminal breast cancer: from biology to treatment. Nat Rev Clin Oncol 10, 494–506 (2013). https://doi.org/10.1038/nrclinonc.2013.124

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