237
Views
9
CrossRef citations to date
0
Altmetric
Review

The evolving role of receptors as predictive biomarkers for metastatic breast cancer

ORCID Icon, &
Pages 121-138 | Received 29 Jun 2018, Accepted 21 Nov 2018, Published online: 03 Dec 2018

References

  • Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.
  • Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.
  • Atkinson AJ, Colburn WA, DeGruttola VG, et al. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69:89–95.
  • FDA-NIH Biomarker Working Group. BEST (biomarkers, endpoints, and other tools) resource. Food and Drug Administration (FDA) and National Institutes of Health (NIH). Silver Spring and Bethesda, MD; 2017.
  • Nicolini A, Ferrari P, Duffy MJ. Prognostic and predictive biomarkers in breast cancer: past, present and future. Semin Cancer Biol. 2018;52:56-73.
  • Donegan WL. Tumor-related prognostic factors for breast cancer. CA Cancer J Clin. 1997;47:28–51.
  • Cianfrocca M. Prognostic and predictive factors in early-stage breast cancer. Oncologist. 2004;9:606–616.
  • Győrffy B, Hatzis C, Sanft T, et al. Multigene prognostic tests in breast cancer: past, present, future. Breast Cancer Res. 2015;17:11.
  • Duffy MJ, O’Donovan N, McDermott E, et al. Validated biomarkers: the key to precision treatment in patients with breast cancer. Breast. 2016;29:192–201.
  • Duffy MJ, Harbeck N, Nap M, et al. Clinical use of biomarkers in breast cancer: updated guidelines from the European Group On Tumor Markers (EGTM). Eur J Cancer. 2017;75:284–298.
  • Schwaederle M, Zhao M, Lee JJ, et al. Impact of precision medicine in diverse cancers: a meta-analysis of phase II clinical trials. J Clin Oncol. 2015;33:3817–3825.
  • Nemere I, Pietras RJ, Blackmore PF. Membrane receptors for steroid hormones: signal transduction and physiological significance. J Cell Biochem. 2003;88:438–445.
  • Marino M, Galluzzo P, Ascenzi P. Estrogen signaling multiple pathways to impact gene transcription. Curr Genomics. 2006;7:497-508.
  • Thomas C, Gustafsson JÅ. The different roles of ER subtypes in cancer biology and therapy. Nat Rev Cancer. 2011;11:597–608.
  • Björnström L, Sjöberg M. Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Mol Endocrinol. 2005;19:833–842.
  • Nicholson RI, Gee JMW. Oestrogen and growth factor cross-talk and endocrine insensitivity and acquired resistance in breast cancer. Br J Cancer. 2000;82:501–513.
  • Arpino G, Wiechmann L, Osborne CK, et al. Crosstalk between the estrogen receptor and the HER tyrosine kinase receptor family: molecular mechanism and clinical implications for endocrine therapy resistance. Endocr Rev. 2008;29:217–233.
  • Elder K, Dixon JMM, Blackmur JP, et al. Endocrine therapy for cancer. Surgery. 2018;36:134–138.
  • Clarke R, Tyson JJ, Dixon JM. Endocrine resistance in breast cancer – an overview and update. Mol Cell Endocrinol. 2015;418:220–234.
  • Clarke R, Leonessa F, Welch JN, et al. Cellular and molecular pharmacology of antiestrogen action and resistance. Pharmacol Rev. 2001;53:25–71.
  • Clarke R, Skaar TC, Bouker KB, et al. Molecular and pharmacological aspects of antiestrogen resistance. J Steroid Biochem Mol Biol. 2001;76:71–84.
  • Carroll JS. Mechanisms of oestrogen receptor (ER) gene regulation in breast cancer. Eur J Endocrinol. 2016;175:R41–9.
  • Mangelsdorf DJ, Thummel C, Beato M, et al. The nuclear receptor superfamily: the second decade. Cell. 1995;83:835–839.
  • Mohammed H, Russell IA, Stark R, et al. Progesterone receptor modulates ERα action in breast cancer. Nature. 2015;523:313–317.
  • Carroll JS, Hickey TE, Tarulli GA, et al. Deciphering the divergent roles of progestogens in breast cancer. Nat Rev Cancer. 2017;17:54–64.
  • Viale G, Regan MM, Maiorano E, et al. 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;25:3846–3852.
  • Olivotto IA, Truong PT, Speers CH, et al. Time to stop progesterone receptor testing in breast cancer management. J Clin Oncol. 2004;22:1769–1770.
  • Ravdin PM, Green S, Dorr TM, et al. Prognostic significance of progesterone receptor levels in estrogen receptor-positive patients with metastatic breast cancer treated with tamoxifen: results of a prospective southwest oncology group study. J Clin Oncol. 1992;10:1284–1291.
  • Nordenskjöld A, Fohlin H, Fornander T, et al. Progesterone receptor positivity is a predictor of long-term benefit from adjuvant tamoxifen treatment of estrogen receptor positive breast cancer. Breast Cancer Res Treat. 2016;160:313–322.
  • Stendahl M, Rydén L, Nordenskjöld B, et al. High progesterone receptor expression correlates to the effect of adjuvant tamoxifen in premenopausal breast cancer patients. Clin Cancer Res. 2006;12:4614–4618.
  • Bardou VJ, Arpino G, Elledge RM, et al. 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;21:1973–1979.
  • Dowsett M, Houghton J, Iden C, et al. Benefit from adjuvant tamoxifen therapy in primary breast cancer patients according oestrogen receptor, progesterone receptor, EGF receptor and HER2 status. Ann Oncol. 2006;17:818–826.
  • Grassadonia A, Vici P, Gamucci T, et al. Long-term outcome of breast cancer patients with pathologic N3a lymph node stage. Breast. 2017;32:79–86.
  • Van Belle V, Van Calster B, Brouckaert O, et al. Qualitative assessment of the progesterone receptor and HER2 improves the Nottingham prognostic index up to 5 years after breast cancer diagnosis. J Clin Oncol. 2010;28:4129–4134.
  • Liu S, Chia SK, Mehl E, et al. Progesterone receptor is a significant factor associated with clinical outcomes and effect of adjuvant tamoxifen therapy in breast cancer patients. Breast Cancer Res Treat. 2010;119:53–61.
  • Salmen J, Neugebauer J, Fasching PA, et al. Pooled analysis of the prognostic relevance of progesterone receptor status in five German cohort studies. Breast Cancer Res Treat. 2014;148:143–151.
  • Fossati R, Confalonieri C, Torri V, et al. Cytotoxic and hormonal treatment for metastatic breast cancer: a systematic review of published randomized trials involving 31,510 women. J Clin Oncol. 1998;16:3439–3460.
  • Mauri D, Pavlidis N, Ioannidis JPA. Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. J Natl Cancer Inst. 2005;97:188–194.
  • Creighton CJ, Kent Osborne C, Van De Vijver MJ, et al. Molecular profiles of progesterone receptor loss in human breast tumors. Breast Cancer Res Treat. 2009;114:287–299.
  • Brennan M, Lim B. (2015). The Actual Role of Receptors as Cancer Markers, Biochemical and Clinical Aspects: Receptors in Breast Cancer. In: Scatena R. (eds) Advances in Cancer Biomarkers. Advances in Experimental Medicine and Biology, vol 867. Springer, Dordrecht.
  • Cui X, Schiff R, Arpino G, et al. Biology of progesterone receptor loss in breast cancer and its implications for endocrine therapy. J Clin Oncol. 2005;23:7721–7735.
  • Finn RS, Dering J, Ginther C, et al. ER+ PR- breast cancer defines a unique subtype of breast cancer that is driven by growth factor signaling and may be more likely to respond to EGFR targeted therapies. J Clin Oncol. 2006;24:514.
  • Mcguire WL. Estrogen receptors in human breast cancer. J Clin Invest. 1973;52:73–77.
  • Horowitz K, McGuire W. Predicting response to endocrine therapy in human breast cancer: a hypothesis. Science. 1975;189:726–727.
  • Dodson A, Parry S, Ibrahim M, et al. Abstract P3–08-16: ER, PR and HER2 biomarkers in UK and Irish clinical breast cancer testing: analysis of results from >168,000 patients. Cancer Res. 2018;78:P3–08–16.
  • Lovekin C, Ellis IO, Locker A, et al. c-erbB-2 oncoprotein expression in primary and advanced breast cancer. Br J Cancer. 1991;63:439–443.
  • Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244:707–712.
  • Rimawi MF, Schiff R, Osborne CK. Targeting HER2 for the treatment of breast cancer. Annu Rev Med. 2015;66:111–128.
  • Slamon D, Clark G, Wong S, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177–182.
  • Thor A. HER2-a discussion of testing approaches in the USA. Ann Oncol. 2001;12(Suppl 1):S101–7.
  • Furrer D, Sanschagrin F, Jacob S, et al. Advantages and disadvantages of technologies for HER2 testing in breast cancer specimens: table 1. Am J Clin Pathol. 2015;144:686–703.
  • Perez EA, Cortés J, Gonzalez-Angulo AM, et al. HER2 testing: current status and future directions. Cancer Treat Rev. 2014;40:276–284.
  • Roche PC, Suman VJ, Jenkins RB, et al. Concordance between local and central laboratory HER2 testing in the breast intergroup trial N9831. J Natl Cancer Inst. 2002;94:855–857.
  • Perez EA, Press MF, Dueck AC, et al. Immunohistochemistry and fluorescence in situ hybridization assessment of HER2 in clinical trials of adjuvant therapy for breast cancer (NCCTG N9831, BCIRG 006, and BCIRG 005). Breast Cancer Res Treat. 2013;138:99–108.
  • Paik S, Bryant J, Tan-Chiu E, et al. Real-world performance of HER2 testing – national surgical adjuvant breast and bowel project experience. J Natl Cancer Inst. 2002;94:852–854.
  • Reddy JC, Reimann JD, Anderson SM, et al. Concordance between central and local laboratory HER2 testing from a community-based clinical study. Clin Breast Cancer. 2006;7:153–157.
  • Perez EA, Suman VJ, Davidson NE, et al. HER2 testing by local, central, and reference laboratories in specimens from the north central cancer treatment group N9831 intergroup adjuvant trial. J Clin Oncol. 2006;24:3032–3038.
  • Vigo S, Mainella A, Sansano M, et al. Correlation between IHC and FISH for HER2/neu assessment in patients with breast cancer. J Clin Oncol. 2008;26:20718.
  • Zoppoli G, Garuti A, Cirmena G, et al. Her2 assessment using quantitative reverse transcriptase polymerase chain reaction reliably identifies Her2 overexpression without amplification in breast cancer cases. J Transl Med. 2017;15:91.
  • Rakha EA, Pinder SE, Bartlett JMS, et al. Updated UK recommendations for HER2 assessment in breast cancer. J Clin Pathol. 2015;68:93–99.
  • Payandeh M, Sadeghi M, Sadeghi E, et al. Is there any concordance between of IHC with FISH in HER2-positive breast cancer patients? Int J Hematol Stem Cell Res. 2017;11:43–48.
  • Wolff AC, Hammond MEH, Allison KH, et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline focused update. arch. Pathol Lab Med. 2018;142:1364-1382.
  • Dawood S, Broglio K, Buzdar AU, et al. Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional-based review. J Clin Oncol. 2010;28:92–98.
  • Chia SK. Neoadjuvant and adjuvant therapy for HER2 positive disease. Am Soc Clin Oncol Educ B. 2015;35:e41–e48.
  • Eroglu Z, Tagawa T, Somlo G. Human epidermal growth factor receptor family-targeted therapies in the treatment of Her2-overexpressing breast cancer. Oncologist. 2014;19:135–150.
  • Martin M, López-Tarruella S. Emerging therapeutic options for HER2-positive breast cancer. Am Soc Clin Oncol Educ B. 2016;36:e64–e70.
  • Dent S, Oyan B, Honig A, et al. HER2-targeted therapy in breast cancer: a systematic review of neoadjuvant trials. Cancer Treat Rev. 2013;39:622–631.
  • Loibl S, Gianni L. HER2-positive breast cancer. Lancet. 2017;389:2415–2429.
  • Park HS, Sohn J, Kim SI, et al. Effects of hormone receptor status on the durable response of trastuzumab-based therapy in metastatic breast cancer. Breast Cancer Res Treat. 2017;163:255–262.
  • Hicks M, Macrae ER, Abdel-Rasoul M, et al. Neoadjuvant dual HER2-targeted therapy with lapatinib and trastuzumab improves pathologic complete response in patients with early stage HER2-positive breast cancer: a meta-analysis of randomized prospective clinical trials. Oncologist. 2015;20:337–343.
  • Gianni L, Pienkowski T, Im Y-H, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (neosphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:25–32.
  • Swain SM, Kim SB, Cortés J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013;14:461–471.
  • Llombart-Cussac A, Cortés J, Paré L, et al. HER2-enriched subtype as a predictor of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer (PAMELA): an open-label, single-group, multicentre, phase 2 trial. Lancet Oncol. 2017;18:545–554.
  • Larionov AA. Current therapies for human epidermal growth factor receptor 2-positive metastatic breast cancer patients. Front Oncol. 2018;8:89.
  • Figueroa-Magalhães MC, Jelovac D, Connolly R, et al. Treatment of HER2-positive breast cancer. Breast. 2014;23:128–136.
  • Callahan R, Hurvitz S. Human epidermal growth factor receptor-2-positive breast cancer: current management of early, advanced, and recurrent disease. Curr Opin Obstet Gynecol. 2011;23:37–43.
  • Schwab RB, Koehler M, Ali SM, et al. Genomic profiling and treatment of HER2+, ER+, PgR+ “triple positive” breast cancer: a case report and literature review. Cancer Treat Res Commun. 2016;9:27–31.
  • Orphanos G, Kountourakis P. Targeting the HER2 Receptor in metastatic breast cancer. Hematol Oncol Stem Cell Ther. 2012;5:127–137.
  • Zardavas D, Irrthum A, Swanton C, et al. Clinical management of breast cancer heterogeneity. Nat Rev Clin Oncol. 2015;12:381–394.
  • Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366:883–892.
  • Diamantis A, Magiorkinis E, Koutselini H. Fine-needle aspiration (FNA) biopsy: historical aspects. Folia Histochem Cytobiol. 2009;47:191–197.
  • Welch DR. Tumor Heterogeneity–A “contemporary concept” founded on historical insights and predictions. Cancer Res. 2016;76:4–6.
  • Greer LT, Rosman M, Mylander WC, et al. Does breast tumor heterogeneity necessitate further immunohistochemical staining on surgical specimens? J. Am Coll Surg Elsevier. 2013;216:239–251.
  • Petrau C, Clatot F, Cornic M, et al. Reliability of prognostic and predictive factors evaluated by needle core biopsies of large breast invasive tumors. Am J Clin Pathol. 2015;144:555–562.
  • Vance GH, Barry TS, Bloom KJ, et al. Genetic heterogeneity in HER2 testing in breast cancer. Arch Pathol Lab Med. 2009;133:611–612.
  • Seol H, Lee HJ, Choi Y, et al. Intratumoral heterogeneity of HER2 gene amplification in breast cancer: its clinicopathological significance. Mod Pathol. 2012;25:938–948.
  • Welch HG, Gorski DH, Albertsen PC. Trends in metastatic breast and prostate cancer — Lessons in cancer dynamics. N Engl J Med. 2015;373:1685–1687.
  • Dixon JM. Endocrine resistance in breast cancer. New J Sci. 2014;2014:1–27.
  • Cobleigh MA, Anderson SJ, Juilan TB, et al. NSABP B-43: a phase III clinical trial to compare trastuzumab (T) given concurrently with radiation therapy (RT) to RT alone for women with HER2+ DCIS resected by lumpectomy (Lx). Jco. 2013;31:Abstract TPS666.
  • Rexer BN, Arteaga CL. Intrinsic and acquired resistance to HER2-targeted therapies in HER2 gene-amplified breast cancer: mechanisms and clinical implications. Crit Rev Oncog. 2012;17:1–16.
  • Sonnenblick A, Pondé N, Piccart M. Metastatic breast cancer: the Odyssey of personalization. Mol Oncol. 2016;10:1147–1159.
  • Ellsworth RE, Blackburn HL, Shriver CD, et al. Molecular heterogeneity in breast cancer: state of the science and implications for patient care. Semin Cell Dev Biol. 2017;64:65–72.
  • Toss A, Palazzo J, Berger A, et al. Clinical-pathological features and treatment modalities associated with recurrence in DCIS and micro-invasive carcinoma: who to treat more and who to treat less. Breast. 2016;29:223–230.
  • Gavilá J, Lopez-Tarruella S, Saura C, et al. SEOM clinical guidelines in metastatic breast cancer 2015. Clin Transl Oncol. 2015;17:946–955.
  • Largillier R, Ferrero JM, Doyen J, et al. Prognostic factors in 1038 women with metastatic breast cancer. Ann Oncol. 2008;19:2012–2019.
  • Cardoso F, Costa A, Norton L, et al. ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2)†. Ann Oncol. 2014;25:1871–1888.
  • Tsimberidou A-M, Wen S, Hong DS, et al. Personalized medicine for patients with advanced cancer in the phase i program at MD anderson: validation and landmark analyses. Clin Cancer Res. 2014;20:4827–4836.
  • Tsimberidou A-M, Iskander NG, Hong DS, et al. Personalized medicine in a phase i clinical trials program: the MD anderson cancer center initiative. Clin Cancer Res. 2012;18:6373–6383.
  • Kaufmann M, Jonat W, Kleeberg U, et al. Goserelin, a depot gonadotrophin-releasing hormone agonist in the treatment of premenopausal patients with metastatic breast cancer. German Zoladex trial group. J Clin Oncol. 1989;7:1113–1119.
  • Kurebayashi J, Sonoo H, Inaji H, et al. Endocrine therapies for patients with recurrent breast cancer: predictive factors for responses to first- and second-line endocrine therapies. Oncology. 2000;59(Suppl 1):31–37.
  • Boér K. Fulvestrant in advanced breast cancer: evidence to date and place in therapy. Ther Adv Med Oncol. 2017;9:465–479.
  • Rugo HS, Rumble RB, Macrae E, et al. Endocrine therapy for hormone receptor-positive metastatic breast cancer: American society of clinical oncology guideline. J Clin Oncol. 2016;34:3069–3103.
  • Fabi A, Malaguti P, Vari S, et al. First-line therapy in HER2 positive metastatic breast cancer: is the mosaic fully completed or are we missing additional pieces? J. Exp Clin Cancer Res BioMed Central. 2016;104.
  • Yao M, Fu P. Advances in anti-HER2 therapy in metastatic breast cancer. Chinese Clin Oncol. 2018;7:27.
  • Collovà E, Ferzi A, Scandurra G, et al. Efficacy of trastuzumab in unselected patients with HER2-positive metastatic breast cancer: a retrospective analysis. Tumori. 2014.
  • Kuukasjärvi T, Karhu R, Tanner M, et al. Genetic heterogeneity and clonal evolution underlying development of asynchronous metastasis in human breast cancer. Cancer Res. 1997;57:1597–1604.
  • Becker TE, Ellsworth RE, Deyarmin B, et al. The genomic heritage of lymph node metastases: implications for clinical management of patients with breast cancer. Ann Surg Oncol. 2008;15:1056–1063.
  • Nik-Zainal S, Van Loo P, Wedge DC, et al. The life history of 21 breast cancers. Cell. 2012;149:994–1007.
  • Valastyan S, Weinberg RAA. Tumor metastasis: molecular insights and evolving paradigms. Cell. 2011;147:275–292.
  • Ng CK, Pemberton HN, Reis-Filho JS. Breast cancer intratumor genetic heterogeneity: causes and implications. Expert Rev Anticancer Ther. 2012;12:1021–1032.
  • Selli C, Dixon JM, Sims AH. Accurate prediction of response to endocrine therapy in breast cancer patients: current and future biomarkers. Breast Cancer Res. 2016;18:118.
  • Nik-Zainal S, Davies H, Staaf J, et al. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature. 2016;534:47–54.
  • Turner NH, Di Leo A. HER2 discordance between primary and metastatic breast cancer: assessing the clinical impact. Cancer Treat Rev. 2013;39:947–957.
  • Aurilio G, Disalvatore D, Pruneri G, et al. A meta-analysis of oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 discordance between primary breast cancer and metastases. Eur J Cancer. 2014;50:277–289.
  • Van Poznak C, Somerfield MR, Bast RC, et al. Use of biomarkers to guide decisions on systemic therapy for women with metastatic breast cancer: American society of clinical oncology clinical practice guideline. J Clin Oncol. 2015;33:2695–2704.
  • Hompes D, Ruers T. Review: incidence and clinical significance of Bevacizumab-related non-surgical and surgical serious adverse events in metastatic colorectal cancer. Eur J Surg Oncol. 2011;37:737–746.
  • Robertson EG, Baxter G. Tumour seeding following percutaneous needle biopsy: the real story!. Clin Radiol. 2011;66:1007–1014.
  • Liebens F, Carly B, Cusumano P, et al. Breast cancer seeding associated with core needle biopsies: a systematic review. Maturitas Elsevier. 2009;62:113–123.
  • Diaz LK, Wiley EL, Venta LA. Are malignant cells displaced by large-gauge needle core biopsy of the breast?. Am J Roentgenol. 1999;173:1303–1313.
  • Pearce DA, Arthur LM, Turnbull AK, et al. Tumour sampling method can significantly influence gene expression profiles derived from neoadjuvant window studies. Sci Rep. 2016;6:29434.
  • Do H, Dobrovic A. Sequence artifacts in DNA from formalin-fixed tissues: causes and strategies for minimization. Clin Chem. 2015;61:64–71.
  • Hadd AG, Houghton J, Choudhary A, et al. Targeted, high-depth, next-generation sequencing of cancer genes in formalin-fixed, paraffin-embedded and fine-needle aspiration tumor specimens. J Mol Diagnostics. 2013;15:234–247.
  • Ma CX, Reinert T, Chmielewska I, et al. Mechanisms of aromatase inhibitor resistance. Nat Rev Cancer. 2015;15:261–275.
  • Osborne CKK, Schiff R. Mechanisms of endocrine resistance in breast cancer. Annu Rev Med. 2011;62:233–247.
  • Araki K, Miyoshi Y. Mechanism of resistance to endocrine therapy in breast cancer: the important role of PI3K/Akt/mTOR in estrogen receptor-positive, HER2-negative breast cancer. Breast Cancer. 2018;25:392–401.
  • Luque-Cabal M, García-Teijido P, Fernández-Pérez Y, et al. Mechanisms behind the resistance to trastuzumab in HER2-amplified breast cancer and strategies to overcome it. Clin Med Insights Oncol. 2016;10:21–30.
  • Gagliato DDM, Jardim DLF, Marchesi MSP, et al. Mechanisms of resistance and sensitivity to anti-HER2 therapies in HER2+ breast cancer. Oncotarget. 2016;7:64431–64446.
  • Sherbet GV. PGR (progesterone receptor). Atlas Genet Cytogenet Oncol Haematol. 2017;21:389-397.
  • Weis KE, Ekena K, Thomas JA, et al. Constitutively active human estrogen receptors containing amino acid substitutions for tyrosine 537 in the receptor protein. Mol Endocrinol. 1996;10:1388–1398.
  • Zhang Q-X-X, Borg A, Wolf DMM, et al. An estrogen receptor mutant with strong hormone-independent activity from a metastatic breast cancer. Cancer Res. 1997;57:1244–1249.
  • Jeselsohn R, Yelensky R, Buchwalter G, et al. Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin Cancer Res. 2014;20:1757–1767.
  • Toy W, Shen Y, Won H, et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet. 2013;45:1439–1445.
  • Toy W, Weir H, Razavi P, et al. Activating ESR1 mutations differentially affect the efficacy of ER antagonists. Cancer Discov. 2017;7:277–287.
  • Li S, Shen D, Shao J, et al. Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts. Cell Rep. 2013;4:1116–1130.
  • Robinson DRDR, Wu Y-M, Vats P, et al. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet. 2013;45:1446–1451.
  • Merenbakh-Lamin K, Ben-Baruch N, Yeheskel A, et al. D538G mutation in estrogen receptor-α: A novel mechanism for acquired endocrine resistance in breast cancer. Cancer Res. 2013;73:6856–6864.
  • Comprehensive molecular portraits of human breast tumours. The Cancer Genome Atlas Network. Nature. 2012;490:61–70.
  • Fanning SW, Mayne CG, Dharmarajan V, et al. Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation. elife. 2016;5:e12792.
  • Jeselsohn R. Are we ready to use ESR1 mutations in clinical practice? Breast Care. 2017;12:309–313.
  • Jeselsohn R, Buchwalter G, De Angelis C, et al. ESR1 mutations—a mechanism for acquired endocrine resistance in breast cancer. Nat Rev Clin Oncol. 2015;12:573–583.
  • Beije N, Sieuwerts AM, Kraan J, et al. Estrogen receptor mutations and splice variants determined in liquid biopsies from metastatic breast cancer patients. Mol Oncol. 2018;12:48–57.
  • Wang P, Bahreini A, Gyanchandani R, et al. Sensitive detection of mono- and polyclonal ESR1 mutations in primary tumors, metastatic lesions, and cell-free DNA of breast cancer patients. Clin Cancer Res. 2016;22:1130–1137.
  • Fribbens C, O’Leary B, Kilburn L, et al. Plasma ESR1 mutations and the treatment of estrogen receptor-Positive advanced breast cancer. J Clin Oncol. 2016;34:2961–2968.
  • Schiavon G, Hrebien S, Garcia-Murillas I, et al. Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer. Sci Transl Med. 2015;7:313ra182.
  • Chandarlapaty S, Chen D, He W, et al. Prevalence of ESR1 mutations in cell-free DNA and outcomes in metastatic breast cancer: a secondary analysis of the BOLERO-2 clinical trial. JAMA Oncol. 2016;2:1310–1315.
  • Takeshita T, Yamamoto Y, Yamamoto-Ibusuki M, et al. Analysis of ESR1 and PIK3CA mutations in plasma cell-free DNA from ER-positive breast cancer patients. Oncotarget. 2017;8:52142–52155.
  • Di Leo A, Jerusalem G, Petruzelka L, et al. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. J Clin Oncol. 2010;28:4594–4600.
  • Wardell SE, Ellis MJ, Alley HM, et al. Efficacy of SERD/SERM hybrid-CDK4/6 inhibitor combinations in models of endocrine therapy-resistant breast cancer. Clin Cancer Res. 2015;21:5121–5130.
  • Wardell SE, Nelson ER, Chao CA, et al. Bazedoxifene exhibits antiestrogenic activity in animal models of tamoxifen-resistant breast cancer: implications for treatment of advanced disease. Clin Cancer Res. 2013;19:2420–2431.
  • Pinkerton JVJV, Thomas S. Use of SERMs for treatment in postmenopausal women. J Steroid Biochem Mol Biol. 2014;142:142–154.
  • Garner F, Shomali M, Paquin D, et al. RAD1901: a novel, orally bioavailable selective estrogen receptor degrader that demonstrates antitumor activity in breast cancer xenograft models. Anticancer Drugs. 2015;26:948–956.
  • Lai A, Kahraman M, Govek S, et al. Identification of GDC-0810 (ARN-810), an orally bioavailable Selective Estrogen Receptor Degrader (SERD) that demonstrates robust activity in tamoxifen-resistant breast cancer xenografts. J Med Chem. 2015;58:4888–4904.
  • Mayer I, Bardia A, Dickler M, et al. Abstract OT3–2-07: phase I study of ARN-810, a novel selective estrogen receptor degrader, in post-menopausal women with locally advanced or metastatic estrogen receptor positive breast cancer. Cancer Res. 2013;73:OT3–2–07.
  • Bihani T, Patel HK, Arlt H, et al. Elacestrant (RAD1901), a Selective Estrogen Receptor Degrader (SERD), has antitumor activity in multiple ER+breast cancer patient-derived xenograft models. Clin Cancer Res. 2017;23:4793–4804.
  • Spoerke JM, Gendreau S, Walter K, et al. Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant. Nat Commun. 2016;7:11579.
  • Dickler M, Villanueva R, Perez Fidalgo J, et al. Abstract PD5–10: a first-in-human phase I study to evaluate the oral selective estrogen receptor degrader (SERD), GDC-0927, in postmenopausal women with estrogen receptor positive (ER+) HER2-negative metastatic breast cancer (BC). Cancer Res. 2018;78:PD5–10.
  • Bardia A, Kabos P, Elledge R, et al. Evaluation of RAD1901, a novel investigational, selective estrogen receptor degrader (SERD), for the treatment of ER-positive (ER+) advanced breast cancer. J Clin Oncol. 2017;35(suppl):abstr1014.
  • Wang Y, Lonard DMDM, Yu Y, et al. Bufalin is a potent small-molecule inhibitor of the steroid receptor coactivators SRC-3 and SRC-1. Cancer Res. 2014;74:1506–1517.
  • Yan F, Yu Y, Chow D-C, et al. Identification of verrucarin a as a potent and selective steroid receptor coactivator-3 small molecule inhibitor. PLoS One. 2014;9:e95243.
  • Hui R, Cornish AL, McClelland RA, et al. Cyclin D1 and estrogen receptor messenger RNA levels are positively correlated in primary breast cancer. Clin Cancer Res. 1996;2:923–928.
  • Finn RS, Dering J, Conklin D, 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. 2009;11:R77.
  • Finn RSRS, Crown JPJP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16:25–35.
  • Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phas. Lancet Oncol. 2016;17:425–439.
  • Albertson DG. Gene amplification in cancer. Trends Genet. 2006;22:447–455.
  • Nembrot M, Quintana B, Mordoh J. Estrogen receptor gene amplification is found in some estrogen receptor-positive human breast tumors. Biochem Biophys Res Commun. 1990;166:601–607.
  • Albertson DG. Conflicting evidence on the frequency of ESR1 amplification in breast cancer. Nat Genet. 2008;40:821–822.
  • Holst F. Estrogen receptor alpha gene amplification in breast cancer: 25 years of debate. World J Clin Oncol. 2016;7:160.
  • Holst F, Stahl PRPR, Ruiz C, et al. Estrogen receptor alpha (ESR1) gene amplification is frequent in breast cancer. Nat Genet. 2007;39:655–660.
  • Brown LA, Hoog J, Chin S-F, et al. ESR1 gene amplification in breast cancer: a common phenomenon? Nat Genet. 2008;40:806–807.
  • Reis-Filho JS, Drury S, Lambros MB, et al. ESR1 gene amplification in breast cancer: a common phenomenon? Nat Genet. 2008;40:809–810.
  • Horlings HM, Bergamaschi A, Nordgard SH, et al. ESR1 gene amplification in breast cancer: a common phenomenon? Nat Genet. 2008;40:807–808.
  • Vincent-Salomon A, Raynal V, Lucchesi C, et al. ESR1 gene amplification in breast cancer: a common phenomenon? Nat Genet. 2008;40:809.
  • Adélaïde J, Finetti P, Charafe-Jauffret E, et al. Absence of ESR1 amplification in a series of breast cancers. Int J Cancer. 2008;123:2970–2972.
  • Tomita S, Zhang Z, Nakano M, et al. Estrogen receptor α gene ESR1 amplification may predict endocrine therapy responsiveness in breast cancer patients. Cancer Sci. 2009;100:1012–1017.
  • Tsiambas E, Georgiannos SN, Salemis N, et al. Significance of estrogen receptor 1 (ESR-1) gene imbalances in colon and hepatocellular carcinomas based on tissue microarrays analysis. Med Oncol. 2011;28:934–940.
  • Moelans CBCB, Monsuur HN, de Pinth JH, et al. ESR1 amplification is rare in breast cancer and is associated with high grade and high proliferation: a multiplex ligation-dependent probe amplification study. Anal Cell Pathol. 2010;33:13–18.
  • Moelans CB, de Weger RA, Monsuur HN, et al. Molecular differences between ductal carcinoma in situ and adjacent invasive breast carcinoma: a multiplex ligation-dependent probe amplification study. Anal Cell Pathol. 2010;33:165–173.
  • Moelans CB, de Weger RA, Monsuur HN, et al. Molecular profiling of invasive breast cancer by multiplex ligation-dependent probe amplification-based copy number analysis of tumor suppressor and oncogenes. Mod Pathol. 2010;23:1029–1039.
  • Thomas C, Gustafsson J-Å. Not enough evidence to include ESR1 amplification. Nat Rev Cancer. 2011;11:823.
  • Holst F, Moelans CB, Filipits M, et al. On the evidence for ESR1 amplification in breast cancer. Nat Rev Cancer. 2012;12:149.
  • Albertson DG. ESR1 amplification in breast cancer: controversy resolved? J Pathol. 2012;227:1–3.
  • Ooi A, Inokuchi M, Harada S, et al. Gene amplification of ESR1 in breast cancers-fact or fiction? A fluorescence in situ hybridization and multiplex ligation-dependent probe amplification study. J Pathol. 2012;227:8–16.
  • Holst F, Stahl P, Hellwinkel O, et al. Reply to “ESR1 gene amplification in breast cancer: a common phenomenon?” Nat Genet. 2008;40:810–812.
  • Holst F, Singer CF. ESR1-amplification- associated estrogen receptor alpha activity in breast cancer. Trends Endocrinol Metab. 2016;27:751–752.
  • Costello JC, Heiser LM, Georgii E, et al. A community effort to assess and improve drug sensitivity prediction algorithms. Nat Biotechnol. 2014;32:1202–1212.
  • Soysal SD, Kilic IB, Regenbrecht CRA, et al. Status of estrogen receptor 1 (ESR1) gene in mastopathy predicts subsequent development of breast cancer. Breast Cancer Res Treat. 2015;151:709–715.
  • Ma CX, Bose R, Ellis MJ. Prognostic and predictive biomarkers of endocrine responsiveness for estrogen receptor positive breast cancer. In: Stearns V, editor. Nov. biomarkers contin. breast cancer. Cham: Springer; 2016. p. 125–154.
  • Rice LW, Jazaeri AA, Shupnik MA. Estrogen receptor mRNA splice variants in pre- and postmenopausal human endometrium and endometrial carcinoma. Gynecol Oncol. 1997;65:149–157.
  • Taylor SE, Martin-Hirsch PL, Martin FL. Oestrogen receptor splice variants in the pathogenesis of disease. Cancer Lett. 2010;288:133–148.
  • Poola I, Speirs V. Expression of alternatively spliced estrogen receptor alpha mRNAs is increased in breast cancer tissues. J Steroid Biochem Mol Biol. 2001;78:459–469.
  • Horvath G, Leser G, Helou K, et al. Function of the exon 7 deletion variant estrogen receptor α protein in an estradiol-resistant, tamoxifen-sensitive human endometrial adenocarcinoma grown in nude mice. Gynecol Oncol. 2002;84:271–279.
  • Zhang QX, Borg A, Fuqua SA. An exon 5 deletion variant of the estrogen receptor frequently coexpressed with wild-type estrogen receptor in human breast cancer. Cancer Res. 1993;53:5882–5884.
  • Zhang Q-X, Hilsenbeck SG, Fuqua SAW, et al. Multiple splicing variants of the estrogen receptor are present in individual human breast tumors. J Steroid Biochem Mol Biol. 1996;59:251–260.
  • Lemieux P, Fuqua S. The role of the estrogen receptor in tumor progression. J Steroid Biochem Mol Biol. 1996;56:87–91.
  • Bollig A, Miksicek RJ. An estrogen receptor-α splicing variant mediates both positive and negative effects on gene transcription. Mol Endocrinol. 2000;14:634–649.
  • Daffada AA, Johnston SR, Nicholls J, et al. Detection of wild type and exon 5-deleted splice variant oestrogen receptor (ER) mRNA in ER-positive and -negative breast cancer cell lines by reverse transcription/polymerase chain reaction. J Mol Endocrinol. 1994;13:265–273.
  • Daffada AA, Johnston SR, Smith IE, et al. Exon 5 deletion variant estrogen receptor messenger RNA expression in relation to tamoxifen resistance and progesterone receptor/pS2 status in human breast cancer. Cancer Res. 1995;55:288–293.
  • Fuqua SA, Fitzgerald SD, Chamness GC, et al. Variant human breast tumor estrogen receptor with constitutive transcriptional activity. Cancer Res. 1991;51:105–109.
  • Chen J-M, Cooper DN, Férec C, et al. Genomic rearrangements in inherited disease and cancer. Semin Cancer Biol. 2010;20:222–233.
  • Stephens PJ, McBride DJ, Lin M-L, et al. Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature. 2009;462:1005–1010.
  • Ewald IP, Ribeiro PLI, Palmero EI, et al. Genomic rearrangements in BRCA1 and BRCA2: a literature review. Genet Mol Biol. 2009;32:437–446.
  • Veeraraghavan J, Tan Y, Cao XX, et al. Recurrent ESR1-CCDC170 rearrangements in an aggressive subset of oestrogen receptor-positive breast cancers. Nat Commun. 2014;5:4577.
  • Dunbier AK, Anderson H, Ghazoui Z, et al. ESR1 is co-expressed with closely adjacent uncharacterised genes spanning a breast cancer susceptibility locus at 6q25.1. Horwitz MS editor PLoS Genet. 2011;7:e1001382.
  • Baselga J, Coleman RE, Cortés J, et al. Advances in the management of HER2-positive early breast cancer. Crit Rev Oncol/Hematol. 2017;119:113–122.
  • Fedele P, Ciccarese M, Surico G, et al. An update on first line therapies for metastatic breast cancer. Expert Opin Pharmacother. 2018;19:243–252.
  • Esteva FJ, Guo H, Zhang S, et al. PTEN, PIK3CA, p-AKT, and p-p70S6K status: association with trastuzumab response and survival in patients with HER2-positive metastatic breast cancer. Am J Pathol. 2010;177:1647–1656.
  • Berns K, Horlings HM, Hennessy BT, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell. 2007;12:395–402.
  • Kataoka Y, Mukohara T, Shimada H, et al. Association between gain-of-function mutations in PIK3CA and resistance to HER2-targeted agents in HER2-amplified breast cancer cell lines. Ann Oncol. 2010;21:255–262.
  • Loibl S, Majewski I, Guarneri V, et al. PIK3CA mutations are associated with reduced pathological complete response rates in primary HER2-positive breast cancer: pooled analysis of 967 patients from five prospective trials investigating lapatinib and trastuzumab. Ann Oncol. 2016;27:1519–1525.
  • Baselga J, Cortés J, Im SA, et al. Biomarker analyses in CLEOPATRA: a phase III, placebo-controlled study of pertuzumab in human epidermal growth factor receptor 2-positive, first-line metastatic breast cancer. J Clin Oncol. 2014;32:3753–3761.
  • Pogue-Geile KL, Song N, Jeong JH, et al. Intrinsic subtypes, PIK3CA mutation, and the degree of benefit from adjuvant trastuzumab in the NSABP B-31 trial. J Clin Oncol. 2015;33:1340–1347.
  • Pohlmann PR, Mayer IA, Mernaugh R. Resistance to trastuzumab in breast cancer. Clin Cancer Res. 2009;15:7479–7491.
  • Tortora G. Mechanisms of resistance to HER2 target therapy. JNCI Monogr. 2011;2011:95–98.
  • Valabrega G, Montemurro F, Aglietta M. Trastuzumab: mechanism of action, resistance and future perspectives in HER2-overexpressing breast cancer. Ann Oncol. 2007;18:977–984.
  • Sagara Y, Mallory MA, Wong S, et al. Survival benefit of breast surgery for low-grade ductal carcinoma in situ. JAMA Surg. 2015;150:739.
  • Arribas J, Baselga J, Pedersen K, et al. p95HER2 and breast cancer. Cancer Res. 2011;1515–1519.
  • Wong ALA, Lee S-C. Mechanisms of resistance to trastuzumab and novel therapeutic strategies in HER2-positive breast cancer. Int J Breast Cancer. 2012;2012:1–13.
  • Sperinde J, Jin X, Banerjee J, et al. Quantitation of p95HER2 in paraffin sections by using a p95-specific antibody and correlation with outcome in a cohort of trastuzumab-treated breast cancer patients. Clin Cancer Res. 2010;16:4226–4235.
  • Bose R, Kavuri SM, Searleman AC, et al. Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov. 2013;3:224–237.
  • Feldinger K, Kong A. Profile of neratinib and its potential in the treatment of breast cancer. Breast Cancer Dove Med Press. 2015;7:147–162.
  • Hyman D, Piha-Paul S, Saura C, et al. Abstract PD2–08: neratinib + fulvestrant in ERBB2-mutant, HER2–non-amplified, estrogen receptor (ER)-positive, metastatic breast cancer (MBC): preliminary analysis from the phase II SUMMIT trial. Cancer Res. 2017;77:PD2–08.
  • Hyman DM, Piha-Paul SA, Won H, et al. HER kinase inhibition in patients with HER2- and HER3-mutant cancers. Nature. 2018;554:189–194.
  • Hanker AB, Brewer MR, Sheehan JH, et al. An acquired HER2 T798I gatekeeper mutation induces resistance to neratinib in a patient with HER2 mutant–Driven breast cancer. Cancer Discov. 2017;7:575–585.
  • Flowers M, Birkey Reffey S, Mertz SA, et al. Obstacles, opportunities and priorities for advancing metastatic breast cancer research. Cancer Res. 2017;77:3386–3390.
  • Crowley E, Di Nicolantonio F, Loupakis F, et al. Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol. 2013;10:472–484.
  • Pantel K, Alix-Panabières C. Real-time liquid biopsy in cancer patients: fact or fiction? Cancer Res. 2013;73:6384–6388.
  • Wong HY, Park BH. Plasma tumor DNA: on your markers, get set, go!. Ann Transl Med. 2014;2:2.
  • Forshew T, Murtaza M, Parkinson C, et al. Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA. Sci Transl Med. 2012;4:136ra68.
  • Grover PK, Cummins AG, Price TJ, et al. Circulating tumour cells: the evolving concept and the inadequacy of their enrichment by EpCAM-based methodology for basic and clinical cancer research. Ann Oncol. 2014;25:1506–1516.
  • Sieuwerts AM, Kraan J, Bolt-De Vries J, et al. Molecular characterization of circulating tumor cells in large quantities of contaminating leukocytes by a multiplex real-time PCR. Breast Cancer Res Treat. 2009;118:455–468.
  • Canzoniero JV, Park BH. Use of cell free DNA in breast oncology. Biochim Biophys Acta. 2016;1865:266–274.
  • Bettegowda C, Sausen M, Leary RJ, et al. Detection of circulating tumor dna in early- and late-stage human malignancies. sci transl med. 2014;6:224ra24.
  • Dawson S-J, Tsui DWY, Murtaza M, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013;368:1199–1209.
  • Diaz LA Jr., Bardelli A. Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol. 2014;32:579–586.
  • Sefrioui D, Perdrix A, Sarafan-Vasseur N, et al. Short report: monitoring ESR1 mutations by circulating tumor DNA in aromatase inhibitor resistant metastatic breast cancer. Int J Cancer. 2015;137:2513–2519.
  • Chu D, Paoletti C, Gersch C, et al. ESR1 mutations in circulating plasma tumor dna from metastatic breast cancer patients. Clin Cancer Res. 2016;22:993–999.
  • Takeshita T, Yamamoto Y, Yamamoto-Ibusuki M, et al. Droplet digital polymerase chain reaction assay for screening of ESR1 mutations in 325 breast cancer specimens. Transl Res. 2015;166:540–553.e2.
  • Board RE, Wardley AM, Dixon JM, et al. Detection of PIK3CA mutations in circulating free DNA in patients with breast cancer. Breast Cancer Res Treat. 2010;120:461–467.
  • Clatot F, Perdrix A, Augusto L, et al. Kinetics, prognostic and predictive values of ESR1 circulating mutations in metastatic breast cancer patients progressing on aromatase inhibitor. Oncotarget. 2016;7:74448–74459.
  • Yanagawa T, Kagara N, Miyake T, et al. Detection of ESR1 mutations in plasma and tumors from metastatic breast cancer patients using next-generation sequencing. Breast Cancer Res Treat. 2017;163:231–240.
  • Newman AMAM, Bratman SVSV, To J, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med. 2014;20:548–554.
  • Tucker T, Marra M, Friedman JM. Massively parallel sequencing: the next big thing in genetic medicine. Am J Hum Genet. 2009;85:142–154.
  • Shendure J, Ji H. Next-generation DNA sequencing. Nat Biotechnol. 2008;26:1135–1145.
  • Schmitt MW, Kennedy SR, Salk JJ, et al. Detection of ultra-rare mutations by next-generation sequencing. Proc Natl Acad Sci U S A. 2012;109:14508–14513.
  • Vogelstein B, Kinzler KW. Digital PCR. Proc Natl Acad Sci USA. 1999;96:9236–9241.
  • Huggett JF, Cowen S, Foy CA. Considerations for digital PCR as an accurate molecular diagnostic tool. Clin Chem. 2015;61:79–88.
  • Kinde I, Wu J, Papadopoulos N, et al. Detection and quantification of rare mutations with massively parallel sequencing. Proc Natl Acad Sci USA. 2011;108:9530–9535.
  • Wang T, Liu JH, Zhang J, et al. A multiplex allele-specific real-time PCR assay for screening of ESR1 mutations in metastatic breast cancer. Exp Mol Pathol. 2015;98:152–157.
  • Morlan J, Baker J, Sinicropi D. Mutation detection by real-time PCR: a simple, robust and highly selective method. PLoS One. 2009;4:e4584. Schrijver I, editor.
  • Gelsomino L, Gu G, Rechoum Y, et al. ESR1 mutations affect anti-proliferative responses to tamoxifen through enhanced cross-talk with IGF signaling. Breast Cancer Res Treat. 2016;157:253–265.
  • Martin LA, Ribas R, Simigdala N, et al. Discovery of naturally occurring ESR1 mutations in breast cancer cell lines modelling endocrine resistance. Nat Commun. 2017;8:1865.
  • Takeshita T, Yamamoto Y, Yamamoto-Ibusuki M, et al. Comparison of ESR1 mutations in tumor tissue and matched plasma samples from metastatic breast cancer patients. Transl Oncol. 2017;10:766–771.
  • Guttery DS, Page K, Hills A, et al. Noninvasive detection of activating estrogen receptor 1 (ESR1) mutations in estrogen receptor-positive metastatic breast cancer. Clin Chem. 2015;61:974–982.
  • Guan X, Ma F, Liu S, et al. Analysis of the hormone receptor status of circulating tumor cell subpopulations based on epithelial-mesenchymal transition: a proof-of-principle study on the heterogeneity of circulating tumor cells. Oncotarget. 2016;7:65993–66002.
  • Fehm T, Hoffmann O, Aktas B, et al. Detection and characterization of circulating tumor cells in blood of primary breast cancer patients by RT-PCR and comparison to status of bone marrow disseminated cells. Breast Cancer Res. 2009;11:R59.
  • Schramm A, Friedl T, Huober J, et al. Abstract OT1–02-02: the DETECT study program – Personalized treatment in metastatic breast cancer based on circulating tumor cells. Cancer Res. 2016;76:OT1–02.
  • Polasik A, Schramm A, Friedl T, et al. Abstract OT3–04-02: DETECT III and IV – Individualized CTC-based therapy of metastatic breast cancer. Cancer Res. 2017;77:OT3-04-02.
  • Polasik A, Schramm A, Friedl TWP, et al. The DETECT study concept: individualized therapy of metastatic breast cancer. J Clin Oncol. 2016;34:TPS634.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.