Review ctDNA and Breast Cancer

  • Florian ClatotEmail author
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 215)


In only few years, circulating tumor DNA (ctDNA) in breast cancer has moved from purely fundamental research to nearby daily use for treatment selection and drug-resistance assessment. Indeed, technical advances and widespread use of next-generation sequencing or digital PCR allowed for detection of very low amount of tumor DNA in bloodstream. The use of ctDNA as liquid biopsy able either to monitor tumor burden under treatment or to overcome tumor heterogeneity and identify potential targetable drivers. Time has come to define how ctDNA can be implemented for early or metastatic breast cancer management. Data from retrospective analyses of prospective trials have recently highlighted the potential advantages but also the limitations of ctDNA, in particular for patients under endocrine therapy.


  1. Allouchery V, Beaussire L, Perdrix A, Sefrioui D, Augusto L, Guillemet C, Sarafan-Vasseur N, Di Fiore F, Clatot F (2018) Circulating ESR1 mutations at the end of aromatase inhibitor adjuvant treatment and after relapse in breast cancer patients. Breast Cancer Res BCR 20:40PubMedCrossRefPubMedCentralGoogle Scholar
  2. Amir E, Miller N, Geddie W, Freedman O, Kassam F, Simmons C, Oldfield M, Dranitsaris G, Tomlinson G, Laupacis A et al (2012) Prospective study evaluating the impact of tissue confirmation of metastatic disease in patients with breast cancer. J Clin Oncol Off J Am Soc Clin Oncol 30:587–592CrossRefGoogle Scholar
  3. André F, Hurvitz S, Fasolo A, Tseng L-M, Jerusalem G, Wilks S, O’Regan R, Isaacs C, Toi M, Burris H et al (2016) Molecular alterations and everolimus efficacy in human epidermal growth factor receptor 2-overexpressing metastatic breast cancers: combined exploratory biomarker analysis from BOLERO-1 and BOLERO-3. J Clin Oncol Off J Am Soc Clin Oncol 34:2115–2124CrossRefGoogle Scholar
  4. Arnedos M, Vicier C, Loi S, Lefebvre C, Michiels S, Bonnefoi H, Andre F (2015) Precision medicine for metastatic breast cancer–limitations and solutions. Nat Rev Clin Oncol 12:693–704PubMedCrossRefPubMedCentralGoogle Scholar
  5. Baselga J, Cortés J, Im S-A, Clark E, Ross G, Kiermaier A, Swain SM (2014) 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 Off J Am Soc Clin Oncol 32:3753–3761CrossRefGoogle Scholar
  6. Baselga J, Im S-A, Iwata H, Cortés J, De Laurentiis M, Jiang Z, Arteaga CL, Jonat W, Clemons M, Ito Y et al (2017) Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 18:904–916PubMedPubMedCentralCrossRefGoogle Scholar
  7. Beaver JA, Jelovac D, Balukrishna S, Cochran R, Croessmann S, Zabransky DJ, Wong HY, Toro PV, Cidado J, Blair BG et al (2014) Detection of cancer DNA in plasma of patients with early-stage breast cancer. Clin Cancer Res Off J Am Assoc Cancer Res 20:2643–2650CrossRefGoogle Scholar
  8. Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, Bartlett BR, Wang H, Luber B, Alani RM et al (2014) Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 6:224ra24PubMedPubMedCentralCrossRefGoogle Scholar
  9. Bihani T, Patel HK, Arlt H, Tao N, Jiang H, Brown J, Purandare DM, Hattersley G, Garner F (2017) Elacestrant (RAD1901), a selective estrogen receptor degrader (SERD), has anti-tumor activity in multiple ER+ breast cancer patient-derived xenograft models. Clin Cancer Res Off J Am Assoc Cancer Res 23(16):4793–4804CrossRefGoogle Scholar
  10. Boeck S, Jung A, Laubender RP, Neumann J, Egg R, Goritschan C, Vehling-Kaiser U, Winkelmann C, Fischer von Weikersthal L, Clemens MR et al (2013) EGFR pathway biomarkers in erlotinib-treated patients with advanced pancreatic cancer: translational results from the randomised, crossover phase 3 trial AIO-PK0104. Br J Cancer 108:469–476PubMedCrossRefPubMedCentralGoogle Scholar
  11. Bose R, Kavuri SM, Searleman AC, Shen W, Shen D, Koboldt DC, Monsey J, Goel N, Aronson AB, Li S et al (2013) Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov 3:224–237PubMedCrossRefPubMedCentralGoogle Scholar
  12. Butler TM, Johnson-Camacho K, Peto M, Wang NJ, Macey TA, Korkola JE, Koppie TM, Corless CL, Gray JW, Spellman PT (2015) Exome sequencing of cell-free DNA from metastatic cancer patients identifies clinically actionable mutations distinct from primary disease. PLoS ONE 10:e0136407PubMedPubMedCentralCrossRefGoogle Scholar
  13. Cancer Genome Atlas Network (2012) Comprehensive molecular portraits of human breast tumours. Nature 490:61–70CrossRefGoogle Scholar
  14. Chandarlapaty S, Chen D, He W, Sung P, Samoila A, You D, Bhatt T, Patel P, Voi M, Gnant M et al (2016) Prevalence of ESR1 mutations in cell-free DNA and outcomes in metastatic breast cancer: a secondary analysis of the BOLERO-2 clinical trial. JAMA Oncol 2:1310–1315PubMedPubMedCentralCrossRefGoogle Scholar
  15. Chen Y-H, Hancock BA, Solzak JP, Brinza D, Scafe C, Miller KD, Radovich M (2017) Next-generation sequencing of circulating tumor DNA to predict recurrence in triple-negative breast cancer patients with residual disease after neoadjuvant chemotherapy. NPJ Breast Cancer 3:24PubMedPubMedCentralCrossRefGoogle Scholar
  16. Cheng J, Holland-Letz T, Wallwiener M, Surowy H, Cuk K, Schott S, Trumpp A, Pantel K, Sohn C, Schneeweiss A et al (2018) Circulating free DNA integrity and concentration as independent prognostic markers in metastatic breast cancer. Breast Cancer Res Treat 169:69–82PubMedCrossRefPubMedCentralGoogle Scholar
  17. Clatot F, Perdrix A, Augusto L, Beaussire L, Delacour J, Calbrix C, Sefrioui D, Viailly P-J, Bubenheim M, Moldovan C et al (2016) Kinetics, prognostic and predictive values of ESR1 circulating mutations in metastatic breast cancer patients progressing on aromatase inhibitor. Oncotarget 7:74448–74459PubMedPubMedCentralCrossRefGoogle Scholar
  18. Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im S-A, Masuda N, Colleoni M, DeMichele A, Loi S, Verma S et al (2016) 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, phase 3 randomised controlled trial. Lancet Oncol 17:425–439PubMedPubMedCentralCrossRefGoogle Scholar
  19. Dawson S-J, Tsui DWY, Murtaza M, Biggs H, Rueda OM, Chin S-F, Dunning MJ, Gale D, Forshew T, Mahler-Araujo B et al (2013) Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med 368:1199–1209CrossRefGoogle Scholar
  20. De Mattos-Arruda L, Weigelt B, Cortes J, Won HH, Ng CKY, Nuciforo P, Bidard F-C, Aura C, Saura C, Peg V et al (2014) Capturing intra-tumor genetic heterogeneity by de novo mutation profiling of circulating cell-free tumor DNA: a proof-of-principle. Ann Oncol Off J Eur Soc Med Oncol 25:1729–1735CrossRefGoogle Scholar
  21. Desmedt C, Fumagalli D, Pietri E, Zoppoli G, Brown D, Nik-Zainal S, Gundem G, Rothé F, Majjaj S, Garuti A et al (2015) Uncovering the genomic heterogeneity of multifocal breast cancer. J Pathol 236:457–466PubMedPubMedCentralCrossRefGoogle Scholar
  22. Diaz LA, Bardelli A (2014) Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol Off J Am Soc Clin Oncol 32:579–586CrossRefGoogle Scholar
  23. Duffy MJ, Evoy D, McDermott EW (2010) CA 15-3: uses and limitation as a biomarker for breast cancer. Clin Chim Acta Int J Clin Chem 411:1869–1874CrossRefGoogle Scholar
  24. Fribbens C, O’Leary B, Kilburn L, Hrebien S, Garcia-Murillas I, Beaney M, Cristofanilli M, Andre F, Loi S, Loibl S et al (2016) Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer. J Clin Oncol Off J Am Soc Clin Oncol 34:2961–2968CrossRefGoogle Scholar
  25. Fribbens C, Garcia Murillas I, Beaney M, Hrebien S, O’Leary B, Kilburn L, Howarth K, Epstein M, Green E, Rosenfeld N et al (2018) Tracking evolution of aromatase inhibitor resistance with circulating tumour DNA analysis in metastatic breast cancer. Ann Oncol Off J Eur Soc Med Oncol 29:145–153CrossRefGoogle Scholar
  26. Fujita N, Nakayama T, Yamamoto N, Kim SJ, Shimazu K, Shimomura A, Maruyama N, Morimoto K, Tamaki Y, Noguchi S (2012) Methylated DNA and total DNA in serum detected by one-step methylation-specific PCR is predictive of poor prognosis for breast cancer patients. Oncology 83:273–282PubMedCrossRefPubMedCentralGoogle Scholar
  27. Fujita N, Kagara N, Yamamoto N, Shimazu K, Shimomura A, Shimoda M, Maruyama N, Naoi Y, Morimoto K, Oda N et al (2014) Methylated DNA and high total DNA levels in the serum of patients with breast cancer following neoadjuvant chemotherapy are predictive of a poor prognosis. Oncol Lett 8:397–403PubMedPubMedCentralCrossRefGoogle Scholar
  28. Garcia-Murillas I, Schiavon G, Weigelt B, Ng C, Hrebien S, Cutts RJ, Cheang M, Osin P, Nerurkar A, Kozarewa I et al (2015) Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Sci Transl Med 7:302ra133PubMedCrossRefPubMedCentralGoogle Scholar
  29. Gevensleben H, Garcia-Murillas I, Graeser MK, Schiavon G, Osin P, Parton M, Smith IE, Ashworth A, Turner NC (2013) Noninvasive detection of HER2 amplification with plasma DNA digital PCR. Clin Cancer Res Off J Am Assoc Cancer Res 19:3276–3284CrossRefGoogle Scholar
  30. Ginsburg O, Bray F, Coleman MP, Vanderpuye V, Eniu A, Kotha SR, Sarker M, Huong TT, Allemani C, Dvaladze A et al (2016) The global burden of women’s cancers: a grand challenge in global health. Lancet Lond Engl 389:847–860CrossRefGoogle Scholar
  31. Guerrero-Zotano A, Mayer IA, Arteaga CL (2016) PI3 K/AKT/mTOR: role in breast cancer progression, drug resistance, and treatment. Cancer Metastasis Rev 35:515–524PubMedCrossRefPubMedCentralGoogle Scholar
  32. Guttery DS, Page K, Hills A, Woodley L, Marchese SD, Rghebi B, Hastings RK, Luo J, Pringle JH, Stebbing J et al (2015) Noninvasive detection of activating estrogen receptor 1 (ESR1) mutations in estrogen receptor-positive metastatic breast cancer. Clin Chem 61:974–982PubMedCrossRefPubMedCentralGoogle Scholar
  33. Hartmaier RJ, Trabucco SE, Priedigkeit N, Chung JH, Parachoniak CA, Vanden Borre P, Morley S, Rosenzweig M, Gay LM, Goldberg ME et al (2018) Recurrent hyperactive ESR1 fusion proteins in endocrine therapy-resistant breast cancer. Ann Oncol Off J Eur Soc Med Oncol 29:872–880CrossRefGoogle Scholar
  34. Heidary M, Auer M, Ulz P, Heitzer E, Petru E, Gasch C, Riethdorf S, Mauermann O, Lafer I, Pristauz G et al (2014) The dynamic range of circulating tumor DNA in metastatic breast cancer. Breast Cancer Res BCR 16:421PubMedCrossRefPubMedCentralGoogle Scholar
  35. Hortobagyi GN, Chen D, Piccart M, Rugo HS, Burris HA, Pritchard KI, Campone M, Noguchi S, Perez AT, Deleu I et al (2016) Correlative analysis of genetic alterations and everolimus benefit in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: results from BOLERO-2. J Clin Oncol Off J Am Soc Clin Oncol 34:419–426CrossRefGoogle Scholar
  36. Huang ZH, Li LH, Hua D (2006) Quantitative analysis of plasma circulating DNA at diagnosis and during follow-up of breast cancer patients. Cancer Lett 243:64–70PubMedCrossRefGoogle Scholar
  37. Jensen JD, Knoop A, Laenkholm AV, Grauslund M, Jensen MB, Santoni-Rugiu E, Andersson M, Ewertz M (2012) PIK3CA mutations, PTEN, and pHER2 expression and impact on outcome in HER2-positive early-stage breast cancer patients treated with adjuvant chemotherapy and trastuzumab. Ann Oncol 23(8):2034–2042. Epub 2011 Dec 15. Scholar
  38. Joensuu H, Bono P, Kataja V, Alanko T, Kokko R, Asola R, Utriainen T, Turpeenniemi-Hujanen T, Jyrkkiö S, Möykkynen K et al (2009) Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer Trial. J Clin Oncol Off J Am Soc Clin Oncol 27:5685–5692CrossRefGoogle Scholar
  39. Joseph JD, Darimont B, Zhou W, Arrazate A, Young A, Ingalla E, Walter K, Blake RA, Nonomiya J, Guan Z et al (2016) The selective estrogen receptor down regulator GDC-0810 is efficacious in diverse models of ER+ breast cancer. ELife 5:e15828PubMedPubMedCentralCrossRefGoogle Scholar
  40. Juric D, Castel P, Griffith M, Griffith OL, Won HH, Ellis H, Ebbesen SH, Ainscough BJ, Ramu A, Iyer G et al (2015) Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor. Nature 518:240–244PubMedCrossRefPubMedCentralGoogle Scholar
  41. Karachaliou N, Mayo-de las Casas C, Queralt C, de Aguirre I, Melloni B, Cardenal F, Garcia-Gomez R, Massuti B, Sánchez JM, Porta R et al (2015) Association of EGFR L858R mutation in circulating free DNA with survival in the EURTAC trial. JAMA Oncol 1:149–157PubMedCrossRefPubMedCentralGoogle Scholar
  42. Kirkizlar E, Zimmermann B, Constantin T, Swenerton R, Hoang B, Wayham N, Babiarz JE, Demko Z, Pelham RJ, Kareht S et al (2015) Detection of clonal and subclonal copy-number variants in cell-free DNA from patients with breast cancer using a massively multiplexed PCR methodology. Transl Oncol 8:407–416PubMedPubMedCentralCrossRefGoogle Scholar
  43. Krop IE, Mayer IA, Ganju V, Dickler M, Johnston S, Morales S, Yardley DA, Melichar B, Forero-Torres A, Lee SC et al (2016) Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 17:811–821PubMedPubMedCentralCrossRefGoogle Scholar
  44. Kuo Y-B, Chen J-S, Fan C-W, Li Y-S, Chan E-C (2014) Comparison of KRAS mutation analysis of primary tumors and matched circulating cell-free DNA in plasmas of patients with colorectal cancer. Clin Chim Acta Int J Clin Chem 433:284–289CrossRefGoogle Scholar
  45. Lefebvre C, Bachelot T, Filleron T, Pedrero M, Campone M, Soria J-C, Massard C, Lévy C, Arnedos M, Lacroix-Triki M et al (2016) Mutational profile of metastatic breast cancers: a retrospective analysis. PLoS Med 13:e1002201PubMedPubMedCentralCrossRefGoogle Scholar
  46. Leon SA, Shapiro B, Sklaroff DM, Yaros MJ (1977) Free DNA in the serum of cancer patients and the effect of therapy. Cancer Res 37:646–650PubMedPubMedCentralGoogle Scholar
  47. Lin Z, Neiswender J, Fang B, Ma X, Zhang J, Hu X (2017) Value of circulating cell-free DNA analysis as a diagnostic tool for breast cancer: a meta-analysis. Oncotarget 8:26625–26636PubMedPubMedCentralGoogle Scholar
  48. Loibl S, von Minckwitz G, Schneeweiss A, Paepke S, Lehmann A, Rezai M, Zahm DM, Sinn P, Khandan F, Eidtmann H et al (2014) PIK3CA mutations are associated with lower rates of pathologic complete response to anti-human epidermal growth factor receptor 2 (her2) therapy in primary HER2-overexpressing breast cancer. J Clin Oncol Off J Am Soc Clin Oncol 32:3212–3220CrossRefGoogle Scholar
  49. Ma CX, Reinert T, Chmielewska I, Ellis MJ (2015) Mechanisms of aromatase inhibitor resistance. Nat Rev Cancer 15:261–275PubMedCrossRefPubMedCentralGoogle Scholar
  50. Ma F, Zhu W, Guan Y, Yang L, Xia X, Chen S, Li Q, Guan X, Yi Z, Qian H et al (2016) ctDNA dynamics: a novel indicator to track resistance in metastatic breast cancer treated with anti-HER2 therapy. Oncotarget 7:66020–66031PubMedPubMedCentralGoogle Scholar
  51. Ma CX, Bose R, Gao F, Freedman RA, Telli ML, Kimmick G, Winer EP, Naughton MJ, Goetz MP, Russell C et al (2017) Neratinib efficacy and circulating tumor DNA detection of HER2 mutations in HER2 non-amplified metastatic breast cancer. Clin Cancer Res Off J Am Assoc Cancer Res 23(19):5687–5695CrossRefGoogle Scholar
  52. Magnani L, Frigè G, Gadaleta RM, Corleone G, Fabris S, Kempe H, Verschure PJ, Barozzi I, Vircillo V, Hong S-P et al (2017) Acquired CYP19A1 amplification is an early specific mechanism of aromatase inhibitor resistance in ERα metastatic breast cancer. Nat Genet 49:444–450PubMedPubMedCentralCrossRefGoogle Scholar
  53. Majewski IJ, Nuciforo P, Mittempergher L, Bosma AJ, Eidtmann H, Holmes E, Sotiriou C, Fumagalli D, Jimenez J, Aura C et al (2015) PIK3CA mutations are associated with decreased benefit to neoadjuvant human epidermal growth factor receptor 2-targeted therapies in breast cancer. J Clin Oncol Off J Am Soc Clin Oncol 33:1334–1339CrossRefGoogle Scholar
  54. Mastoraki S, Strati A, Tzanikou E, Chimonidou M, Politaki E, Voutsina A, Psyrri A, Georgoulias V, Lianidou E (2018) ESR1 methylation: a liquid biopsy-based epigenetic assay for the follow-up of patients with metastatic breast cancer receiving endocrine treatment. Clin Cancer Res Off J Am Assoc Cancer Res 24:1500–1510CrossRefGoogle Scholar
  55. Merenbakh-Lamin K, Ben-Baruch N, Yeheskel A, Dvir A, Soussan-Gutman L, Jeselsohn R, Yelensky R, Brown M, Miller VA, Sarid D et al (2013) D538G mutation in estrogen receptor-α: a novel mechanism for acquired endocrine resistance in breast cancer. Cancer Res 73:6856–6864PubMedCrossRefPubMedCentralGoogle Scholar
  56. Mouliere F, Chandrananda D, Piskorz AM, Moore EK, Morris J, Ahlborn LB, Mair R, Goranova T, Marass F, Heider K et al (2018) Enhanced detection of circulating tumor DNA by fragment size analysis. Sci. Transl. Med. 10:eaat4921PubMedPubMedCentralCrossRefGoogle Scholar
  57. Moynahan ME, Chen D, He W, Sung P, Samoila A, You D, Bhatt T, Patel P, Ringeisen F, Hortobagyi GN et al (2017) Correlation between PIK3CA mutations in cell-free DNA and everolimus efficacy in HR(+), HER2(−) advanced breast cancer: results from BOLERO-2. Br J Cancer 116:726–730PubMedPubMedCentralCrossRefGoogle Scholar
  58. Murtaza M, Dawson S-J, Tsui DWY, Gale D, Forshew T, Piskorz AM, Parkinson C, Chin S-F, Kingsbury Z, Wong ASC et al (2013) Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 497:108–112CrossRefGoogle Scholar
  59. Murtaza M, Dawson S-J, Pogrebniak K, Rueda OM, Provenzano E, Grant J, Chin S-F, Tsui DWY, Marass F, Gale D et al (2015) Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer. Nat Commun 6:8760PubMedPubMedCentralCrossRefGoogle Scholar
  60. Nik-Zainal S, Davies H, Staaf J, Ramakrishna M, Glodzik D, Zou X, Martincorena I, Alexandrov LB, Martin S, Wedge DC et al (2016) Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature 534:47–54PubMedPubMedCentralCrossRefGoogle Scholar
  61. O’Leary B, Hrebien S, Morden JP, Beaney M, Fribbens C, Huang X, Liu Y, Bartlett CH, Koehler M, Cristofanilli M et al (2018a) Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer. Nat Commun 9:896PubMedPubMedCentralCrossRefGoogle Scholar
  62. O’Leary B, Cutts RJ, Liu Y, Hrebien S, Huang X, Fenwick K, André F, Loibl S, Loi S, Garcia-Murillas I et al (2018b) The genetic landscape and clonal evolution of breast cancer resistance to palbociclib plus fulvestrant in the PALOMA-3 trial. Cancer Discov 8:1390–1403PubMedPubMedCentralCrossRefGoogle Scholar
  63. Olsson E, Winter C, George A, Chen Y, Howlin J, Tang M-HE, Dahlgren M, Schulz R, Grabau D, van Westen D et al (2015) Serial monitoring of circulating tumor DNA in patients with primary breast cancer for detection of occult metastatic disease. EMBO Mol Med 7:1034–1047PubMedPubMedCentralCrossRefGoogle Scholar
  64. Oshiro C, Kagara N, Naoi Y, Shimoda M, Shimomura A, Maruyama N, Shimazu K, Kim SJ, Noguchi S (2015) PIK3CA mutations in serum DNA are predictive of recurrence in primary breast cancer patients. Breast Cancer Res Treat 150:299–307PubMedCrossRefPubMedCentralGoogle Scholar
  65. Pakdel F, Reese JC, Katzenellenbogen BS (1993) Identification of charged residues in an N-terminal portion of the hormone-binding domain of the human estrogen receptor important in transcriptional activity of the receptor. Mol Endocrinol Baltim Md 7:1408–1417Google Scholar
  66. Paoletti C, Schiavon G, Dolce EM, Darga EP, Carr TH, Geradts J, Hoch M, Klinowska T, Lindemann J, Marshall G et al (2018) Circulating biomarkers and resistance to endocrine therapy in metastatic breast cancers: correlative results from AZD9496 Oral SERD Phase I trial. Clin Cancer Res Off J Am Assoc Cancer Res 24:5860–5872CrossRefGoogle Scholar
  67. Perez EA, Dueck AC, McCullough AE, Chen B, Geiger XJ, Jenkins RB, Lingle WL, Davidson NE, Martino S, Kaufman PA et al (2013) Impact of PTEN protein expression on benefit from adjuvant trastuzumab in early-stage human epidermal growth factor receptor 2-positive breast cancer in the North Central Cancer Treatment Group N9831 trial. J Clin Oncol Off J Am Soc Clin Oncol 31:2115–2122CrossRefGoogle Scholar
  68. Petrau C, Clatot F, Cornic M, Berghian A, Veresezan L, Callonnec F, Baron M, Veyret C, Laberge S, Thery J-C et al (2015) Reliability of prognostic and predictive factors evaluated by needle core biopsies of large breast invasive tumors. Am J Clin Pathol 144:555–562PubMedCrossRefPubMedCentralGoogle Scholar
  69. Petrelli F, Tomasello G, Barni S, Lonati V, Passalacqua R, Ghidini M (2017) Clinical and pathological characterization of HER2 mutations in human breast cancer: a systematic review of the literature. Breast Cancer Res Treat 166(2):339–349PubMedCrossRefPubMedCentralGoogle Scholar
  70. Phallen J, Sausen M, Adleff V, Leal A, Hruban C, White J, Anagnostou V, Fiksel J, Cristiano S, Papp E et al (2017) Direct detection of early-stage cancers using circulating tumor DNA. Sci Transl Med 9:eaan2415PubMedPubMedCentralCrossRefGoogle Scholar
  71. Pogue-Geile KL, Song N, Jeong J-H, Gavin PG, Kim S-R, Blackmon NL, Finnigan M, Rastogi P, Fehrenbacher L, Mamounas EP et al (2015) Intrinsic subtypes, PIK3CA mutation, and the degree of benefit from adjuvant trastuzumab in the NSABP B-31 trial. J Clin Oncol Off J Am Soc Clin Oncol 33:1340–1347CrossRefGoogle Scholar
  72. Riva F, Bidard F-C, Houy A, Saliou A, Madic J, Rampanou A, Hego C, Milder M, Cottu P, Sablin M-P et al (2017) Patient-specific circulating tumor DNA detection during Neoadjuvant chemotherapy in triple-negative breast cancer. Clin Chem 63:691–699PubMedCrossRefPubMedCentralGoogle Scholar
  73. Robinson DR, Wu Y-M, Vats P, Su F, Lonigro RJ, Cao X, Kalyana-Sundaram S, Wang R, Ning Y, Hodges L et al (2013) Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet 45:1446–1451PubMedPubMedCentralCrossRefGoogle Scholar
  74. Robson M, Im S-A, Senkus E, Xu B, Domchek SM, Masuda N, Delaloge S, Li W, Tung N, Armstrong A et al (2017) Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med 377(6):523–533PubMedCrossRefPubMedCentralGoogle Scholar
  75. Schiavon G, Hrebien S, Garcia-Murillas I, Cutts RJ, Pearson A, Tarazona N, Fenwick K, Kozarewa I, Lopez-Knowles E, Ribas R et al (2015) Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer. Sci Transl Med 7:313ra182PubMedPubMedCentralCrossRefGoogle Scholar
  76. Schwarzenbach H, Pantel K (2015) Circulating DNA as biomarker in breast cancer. Breast Cancer Res BCR 17:136PubMedCrossRefPubMedCentralGoogle Scholar
  77. Sefrioui D, Perdrix A, Sarafan-Vasseur N, Dolfus C, Dujon A, Picquenot J-M, Delacour J, Cornic M, Bohers E, Leheurteur M et al (2015) Short report: monitoring ESR1 mutations by circulating tumor DNA in aromatase inhibitor resistant metastatic breast cancer. Int J Cancer J Int Cancer 137(10):2513–2519CrossRefGoogle Scholar
  78. Sefrioui D, Beaussire L, Clatot F, Delacour J, Perdrix A, Frebourg T, Michel P, Di Fiore F, Sarafan-Vasseur N (2017) Heparinase enables reliable quantification of circulating tumor DNA from heparinized plasma samples by droplet digital PCR. Clin Chim Acta Int J Clin Chem 472:75–79CrossRefGoogle Scholar
  79. Senkus E, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, Rutgers E, Zackrisson S, Cardoso F, Guidelines Committee ESMO (2015) Primary breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol Off J Eur Soc Med Oncol 26(Suppl 5):v8–30CrossRefGoogle Scholar
  80. Shaw JA, Smith BM, Walsh T, Johnson S, Primrose L, Slade MJ, Walker RA, Coombes RC (2000) Microsatellite alterations plasma DNA of primary breast cancer patients. Clin Cancer Res Off J Am Assoc Cancer Res 6:1119–1124Google Scholar
  81. Silva C, Caramelo O, Almeida-Santos T, Ribeiro Rama AC (2016) Factors associated with ovarian function recovery after chemotherapy for breast cancer: a systematic review and meta-analysis. Hum Reprod Oxf Engl 31:2737–2749CrossRefGoogle Scholar
  82. Skol AD, Sasaki MM, Onel K (2016) The genetics of breast cancer risk in the post-genome era: thoughts on study design to move past BRCA and towards clinical relevance. Breast Cancer Res BCR 18:99PubMedCrossRefPubMedCentralGoogle Scholar
  83. Spoerke JM, Gendreau S, Walter K, Qiu J, Wilson TR, Savage H, Aimi J, Derynck MK, Chen M, Chan IT et al (2016) Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant. Nat Commun 7:11579PubMedPubMedCentralCrossRefGoogle Scholar
  84. Tangvarasittichai O, Jaiwang W, Tangvarasittichai S (2015) The plasma DNA concentration as a potential breast cancer screening marker. Indian J Clin Biochem IJCB 30:55–58PubMedCrossRefPubMedCentralGoogle Scholar
  85. Thierry AR, Mouliere F, El Messaoudi S, Mollevi C, Lopez-Crapez E, Rolet F, Gillet B, Gongora C, Dechelotte P, Robert B et al (2014) Clinical validation of the detection of KRAS and BRAF mutations from circulating tumor DNA. Nat Med 20:430–435PubMedPubMedCentralCrossRefGoogle Scholar
  86. Thompson AM, Jordan LB, Quinlan P, Anderson E, Skene A, Dewar JA, Purdie CA, Breast Recurrence in Tissues Study Group (2010) Prospective comparison of switches in biomarker status between primary and recurrent breast cancer: the Breast Recurrence In Tissues Study (BRITS). Breast Cancer Res BCR 12:R92PubMedCrossRefPubMedCentralGoogle Scholar
  87. Toy W, Shen Y, Won H, Green B, Sakr RA, Will M, Li Z, Gala K, Fanning S, King TA et al (2013) ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet 45:1439–1445PubMedPubMedCentralCrossRefGoogle Scholar
  88. Toy W, Weir H, Razavi P, Lawson M, Goeppert AU, Mazzola AM, Smith A, Wilson J, Morrow C, Wong WL et al (2017) Activating ESR1 mutations differentially affect the efficacy of ER antagonists. Cancer Discov 7:277–287PubMedCrossRefPubMedCentralGoogle Scholar
  89. Umetani N, Giuliano AE, Hiramatsu SH, Amersi F, Nakagawa T, Martino S, Hoon DSB (2006) Prediction of breast tumor progression by integrity of free circulating DNA in serum. J Clin Oncol Off J Am Soc Clin Oncol 24:4270–4276CrossRefGoogle Scholar
  90. Visvanathan K, Fackler MS, Zhang Z, Lopez-Bujanda ZA, Jeter SC, Sokoll LJ, Garrett-Mayer E, Cope LM, Umbricht CB, Euhus DM et al (2017) Monitoring of serum DNA methylation as an early independent marker of response and survival in metastatic breast cancer: TBCRC 005 prospective biomarker study. J Clin Oncol Off J Am Soc Clin Oncol 35:751–758CrossRefGoogle Scholar
  91. Wan JCM, Massie C, Garcia-Corbacho J, Mouliere F, Brenton JD, Caldas C, Pacey S, Baird R, Rosenfeld N (2017) Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nat Rev Cancer 17:223–238PubMedCrossRefPubMedCentralGoogle Scholar
  92. Wardell SE, Ellis MJ, Alley HM, Eisele K, VanArsdale T, Dann SG, Arndt KT, Primeau T, Griffin E, Shao J et al (2015) Efficacy of SERD/SERM hybrid-CDK4/6 inhibitor combinations in models of endocrine therapy-resistant breast cancer. Clin Cancer Res Off J Am Assoc Cancer Res 21:5121–5130CrossRefGoogle Scholar
  93. Weigelt B, Comino-Méndez I, de Bruijn I, Tian L, Meisel JL, Garcia-Murillas I, Fribbens C, Cutts R, Martelotto LG, Ng CKY et al (2017) Diverse BRCA1 and BRCA2 reversion mutations in circulating cell-free DNA of therapy-resistant breast or ovarian cancer. Clin Cancer Res Off J Am Assoc Cancer Res 23(21):6708–6720CrossRefGoogle Scholar
  94. Weir HM, Bradbury RH, Lawson M, Rabow AA, Buttar D, Callis RJ, Curwen JO, de Almeida C, Ballard P, Hulse M et al (2016) AZD9496: an oral estrogen receptor inhibitor that blocks the growth of ER-positive and ESR1-mutant breast tumors in preclinical models. Cancer Res 76:3307–3318PubMedCrossRefPubMedCentralGoogle Scholar
  95. Weis KE, Ekena K, Thomas JA, Lazennec G, Katzenellenbogen BS (1996) Constitutively active human estrogen receptors containing amino acid substitutions for tyrosine 537 in the receptor protein. Mol Endocrinol Baltim Md 10:1388–1398Google Scholar
  96. Yanagawa T, Kagara N, Miyake T, Tanei T, Naoi Y, Shimoda M, Shimazu K, Kim SJ, Noguchi S (2017) Detection of ESR1 mutations in plasma and tumors from metastatic breast cancer patients using next-generation sequencing. Breast Cancer Res Treat 163:231–240PubMedCrossRefPubMedCentralGoogle Scholar
  97. Yates LR, Gerstung M, Knappskog S, Desmedt C, Gundem G, Van Loo P, Aas T, Alexandrov LB, Larsimont D, Davies H et al (2015) Subclonal diversification of primary breast cancer revealed by multiregion sequencing. Nat Med 21:751–759PubMedPubMedCentralCrossRefGoogle Scholar
  98. Zhang QX, Borg A, Wolf DM, Oesterreich S, Fuqua SA (1997) An estrogen receptor mutant with strong hormone-independent activity from a metastatic breast cancer. Cancer Res 57:1244–1249PubMedPubMedCentralGoogle Scholar
  99. Zhou Y, Wang C, Zhu H, Lin Y, Pan B, Zhang X, Huang X, Xu Q, Xu Y, Sun Q (2016) Diagnostic accuracy of PIK3CA mutation detection by circulating free DNA in breast cancer: a meta-analysis of diagnostic test accuracy. PLoS ONE 11:e0158143PubMedPubMedCentralCrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Department of Medical OncologyCentre Henri BecquerelRouen Cedex 1France
  2. 2.Normandie Univ, UNIROUEN, Inserm U1245, IRON GroupNormandy Centre for Genomic and Personalized Medicine, Rouen University HospitalRouenFrance

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