Emerging Role of Genomics and Cell-Free DNA in Breast Cancer
Precision Medicine is gaining momentum as the future gold standard healthcare strategy as it enables treatment optimization and consequently a potential improvement for quality of life and survival. This paradigm shift was possible thanks to new high-throughput genomics technologies, which provide prognostic and predictive information on tumor biology and potential treatment options, as standard pathological procedures are unable to capture both spatial and temporal tumor heterogeneity. As a result of decreasing costs, both solid and liquid-based genomics have an increasingly important role in clinical trials’ screening procedures and are gradually being incorporated into clinical practice. Notwithstanding the great potential, its clinical utility is still a matter of debate and clinicians need to be aware of caveats in interpreting resulting data.
KeywordsCirculating tumor DNA Biomarkers Translational medicine Precision medicine Breast cancer
Compliance with Ethical Standards
Conflict of Interest
Lorenzo Gerratana has received investigator-initiated study support from Eisai, has received compensation from Eli Lilly & Co. for participation on an advisory board, and has received reimbursement for travel expenses from Menarini Silicon Biosystems.
Andrew A. Davis has received reimbursement for travel expenses from Menarini Silicon Biosystems.
Ami N. Shah declares that she has no conflict of interest.
Chenyu Lin declares that he has no conflict of interest.
Carla Corvaja declares that she has no conflict of interest.
Massimo Cristofanilli declares that he has no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
References and recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.Human Genome Project Completion: Frequently Asked Questions - National Human Genome Research Institute (NHGRI) [Internet]. [cited 2019 Feb 16]. Available from: https://www.genome.gov/11006943/human-genome-project-completion-frequently-asked-questions/
- 2.The Cost of Sequencing a Human Genome - National Human Genome Research Institute (NHGRI) [Internet]. [cited 2019 Feb 14]. Available from: https://www.genome.gov/sequencingcosts/
- 5.Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature [internet]. 2012;490:61–70. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23000897.
- 6.Stephens PJ, Tarpey PS, Davies H, Van Loo P, Greenman C, Wedge DC, et al. The landscape of cancer genes and mutational processes in breast cancer. Nature [Internet]. 2012;486:400–4. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22722201.
- 7.Shah SP, Roth A, Goya R, Oloumi A, Ha G, Zhao Y, et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature [internet]. 2012;486:395–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22495314.
- 8.Nik-Zainal S, Davies H, Staaf J, Ramakrishna M, Glodzik D, Zou X, et al. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature [internet]. 2016;534:47–54. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27135926.
- 11.Liang X, Vacher S, Boulai A, Bernard V, Baulande S, Bohec M, et al. Targeted next-generation sequencing identifies clinically relevant somatic mutations in a large cohort of inflammatory breast cancer. Breast Cancer Res [Internet]. 2018;20:88. Available from: https://doi.org/10.1186/s13058-018-1007-x
- 12.Angus L, Wilting S, Riet J van, Smid M, Steenbruggen T, Tjan-Heijnen V, et al. Abstract GS1–07: the genomic landscape of 501 metastatic breast cancer patients. Cancer Res [Internet]. American Association for Cancer Research; 2019 [cited 2019 Feb 16];79:GS1–07. Available from: http://cancerres.aacrjournals.org/content/79/4_Supplement/GS1-07
- 13.O’Leary B, Cutts RJ, Liu Y, Hrebien S, Huang X, Fenwick K, et al. The genetic landscape and clonal evolution of breast cancer resistance to palbociclib plus fulvestrant in the PALOMA-3 trial. Cancer Discov [Internet]. 2018;8:1390–403. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30206110.CrossRefGoogle Scholar
- 14.••Fribbens C, O’Leary B, Kilburn L, Hrebien S, Garcia-Murillas I, Beaney M, et al. Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast Cancer. J Clin Oncol [Internet]. 2016;34:2961–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27269946. Applicability of liquid biopsy for disease monitoring and early resistance detection.
- 15.Spoerke JM, Gendreau S, Walter K, Qiu J, Wilson TR, Savage H, et al. Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant. Nat Commun [Internet]. 2016;7:11579. Available from: http://www.nature.com/articles/ncomms11579
- 16.Chandarlapaty S, Chen D, He W, Sung P, Samoila A, You D, 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 [internet]. 2016;2:1310–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27532364.CrossRefGoogle Scholar
- 17.Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im S-A, Masuda N, 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 [Internet]. 2016;17:425–39. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26947331.
- 18.Malone KE, Daling JR, Doody DR, Hsu L, Bernstein L, Coates RJ, et al. Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35 to 64 years. Cancer Res [Internet]. 2006;66:8297–308. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16912212.CrossRefGoogle Scholar
- 21.Winter C, Nilsson MP, Olsson E, George AM, Chen Y, Kvist A, et al. Targeted sequencing of BRCA1 and BRCA2 across a large unselected breast cancer cohort suggests that one-third of mutations are somatic. Ann Oncol Off J Eur Soc Med Oncol [Internet]. 2016;27:1532–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27194814.CrossRefGoogle Scholar
- 22.Ross JS, Gay LM, Wang K, Ali SM, Chumsri S, Elvin JA, et al. Nonamplification ERBB2 genomic alterations in 5605 cases of recurrent and metastatic breast cancer: an emerging opportunity for anti-HER2 targeted therapies. Cancer [Internet]. 2016;122:2654–62. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27284958.CrossRefGoogle Scholar
- 23.Hyman DM, Piha-Paul SA, Won H, Rodon J, Saura C, Shapiro GI, et al. HER kinase inhibition in patients with HER2- and HER3-mutant cancers. Nature [Internet]. 2018;554:189–94. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29420467.
- 24.Ross J, Chung J, Elvin J, Vergilio J-A, Ramkissoon S, Suh J, et al. Abstract P2–09-15: NTRK fusions in breast cancer: Clinical, pathologic and genomic findings. Cancer Res [Internet]. 2018;78:P2–09-15-P2–09-15. Available from: https://doi.org/10.1158/1538-7445.SABCS17-P2-09-15
- 25.Goodman AM, Kato S, Bazhenova L, Patel SP, Frampton GM, Miller V, et al. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther [internet]. 2017;16:2598–608. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28835386.CrossRefGoogle Scholar
- 26.Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SAJR, Behjati S, Biankin A V, et al. Signatures of mutational processes in human cancer. Nature [internet]. 2013;500:415–21. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23945592.
- 29.Linnarsson S. Recent advances in DNA sequencing methods – general principles of sample preparation. Exp Cell Res [Internet]. 2010;316:1339–43 Available from: https://linkinghub.elsevier.com/retrieve/pii/S0014482710000984.CrossRefGoogle Scholar
- 31.Wagle N, Berger MF, Davis MJ, Blumenstiel B, DeFelice M, Pochanard P, Ducar M, van Hummelen P, MacConaill LE, Hahn WC, Meyerson M, Gabriel SB, Garraway LA High-throughput detection of actionable genomic alterations in clinical tumor samples by targeted, Massively Parallel Sequencing Cancer Discov [Internet] 2012;2:82–93. Available from: https://doi.org/10.1158/2159-8290.CD-11-0184 CrossRefGoogle Scholar
- 32.Genomic Testing [Internet]. [cited 2019 Feb 13]. Available from: https://www.foundationmedicine.com/genomic-testing
- 36.Thompson JF, Steinmann KE. Single Molecule Sequencing with a HeliScope Genetic Analysis System. In: Single molecule sequencing with a HeliScope genetic analysis system. Curr Protoc Mol biol [internet]. Hoboken, NJ: John Wiley & Sons, Inc.; 2010. https://doi.org/10.1002/0471142727.mb0710s92.CrossRefGoogle Scholar
- 37.Rhoads A, Au KF. PacBio sequencing and its applications. Genomics Proteomics Bioinformatics [Internet]. 2015;13:278–89 Available from: https://linkinghub.elsevier.com/retrieve/pii/S1672022915001345.CrossRefGoogle Scholar
- 38.Morganti S, Tarantino P, Ferraro E, D’Amico P, Viale G, Trapani D, et al. Complexity of genome sequencing and reporting: next generation sequencing (NGS) technologies and implementation of precision medicine in real life. Crit Rev Oncol Hematol [Internet]. 2019;133:171–82 Available from: https://linkinghub.elsevier.com/retrieve/pii/S1040842818304220.CrossRefGoogle Scholar
- 39.Alioto TS, Buchhalter I, Derdak S, Hutter B, Eldridge MD, Hovig E, et al. A comprehensive assessment of somatic mutation detection in cancer using whole-genome sequencing. Nat Commun [Internet]. 2015;6:10001. Available from: http://www.nature.com/articles/ncomms10001
- 41.Rusch M, Nakitandwe J, Shurtleff S, Newman S, Zhang Z, Edmonson MN, et al. Clinical cancer genomic profiling by three-platform sequencing of whole genome, whole exome and transcriptome. Nat Commun [Internet]. 2018;9:3962 Available from: http://www.nature.com/articles/s41467-018-06485-7.CrossRefGoogle Scholar
- 43.Belkadi A, Bolze A, Itan Y, Cobat A, Vincent QB, Antipenko A, Shang L, Boisson B, Casanova JL, Abel L Whole-genome sequencing is more powerful than whole-exome sequencing for detecting exome variants. Proc Natl Acad Sci [Internet] 2015;112:5473–5478. Available from: https://doi.org/10.1073/pnas.1418631112 CrossRefGoogle Scholar
- 45.Davalos V, Martinez-Cardus A, Esteller M. The epigenomic revolution in breast cancer. Am J Pathol [Internet]. 2017;187:2163–74 Available from: https://linkinghub.elsevier.com/retrieve/pii/S0002944017305825.CrossRefGoogle Scholar
- 47.Buono G, Gerratana L, Bulfoni M, Provinciali N, Basile D, Giuliano M, et al. Circulating tumor DNA analysis in breast cancer: is it ready for prime-time? Cancer Treat Rev [Internet]. 2019; Available from: https://linkinghub.elsevier.com/retrieve/pii/S0305737219300088 Google Scholar
- 48.Chae YK, Davis AA, Jain S, Santa-Maria C, Flaum L, Beaubier N, et al. Concordance of genomic alterations by next-generation sequencing in tumor tissue versus circulating tumor DNA in breast cancer. Mol Cancer Ther [Internet]. American Association for Cancer Research; 2017 [cited 2018 Feb 27];16:1412–20. Available from: https://doi.org/10.1158/1535-7163.MCT-17-0061 CrossRefGoogle Scholar
- 50.Zill O, Banks K, Fairclough S, Mortimer S, Vowles J, Mokhtari R, et al. The landscape of actionable genomic alterations in cell-free circulating tumor DNA from 21,807 advanced cancer patients. bioRxiv [Internet]. Cold Spring Harbor Laboratory; 2017 [cited 2018 Feb 28];233205. Available from: https://www.biorxiv.org/content/early/2017/12/12/233205?rss=1&utm_source=dlvr.it&utm_medium=twitter
- 51.Martínez-Galán J, Torres-Torres B, Núñez MI, López-Peñalver J, Del Moral R, Ruiz De Almodóvar JM, et al. ESR1 gene promoter region methylation in free circulating DNA and its correlation with estrogen receptor protein expression in tumor tissue in breast cancer patients. BMC Cancer [Internet]. 2014;14:59. Available from: https://doi.org/10.1186/1471-2407-14-59
- 52.Schiavon G, Hrebien S, Garcia-Murillas I, Cutts RJ, Pearson A, Tarazona N, et al. Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer. Sci Transl Med [Internet]. 2015;7:313ra182. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26560360.
- 55.Chandarlapaty S, Chen D, He W, Sung P, Samoila A, You D, Bhatt T, Patel P, Voi M, Gnant M, Hortobagyi G, Baselga J, Moynahan ME 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 [Internet] 2016;2:1310–1315. Available from: https://doi.org/10.1001/jamaoncol.2016.1279 CrossRefGoogle Scholar
- 56.Mastoraki S, Strati A, Tzanikou E, Chimonidou M, Politaki E, Voutsina A, et al. ESR1 methylation: a liquid biopsy–based epigenetic assay for the follow-up of patients with metastatic breast cancer receiving endocrine treatment. Clin Cancer Res [Internet]. 2018 [cited 2019 Jan 1];24:1500–10. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29284708.CrossRefGoogle Scholar
- 57.••André F, Ciruelos EM, Rubovszky G, Campone M, Loibl S, Rugo HS, et al. LBA3_PRAlpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): results of the phase III SOLAR-1 trial. Ann Oncol [internet]. 2018;29. Available from: https://doi.org/10.1093/annonc/mdy424.010/5141523. Use of cancer genomics as predictive assessment for targeted treatment response.
- 58.Baselga J, Dent SF, Cortés J, Im Y-H, Diéras V, Harbeck N, et al. Phase III study of taselisib (GDC-0032) + fulvestrant (FULV) v FULV in patients (pts) with estrogen receptor (ER)-positive, PIK3CA -mutant (MUT), locally advanced or metastatic breast cancer (MBC): Primary analysis from SANDPIPER. J Clin Oncol [Internet]. 2018;36:LBA1006-LBA1006. Available from: https://doi.org/10.1200/JCO.2018.36.18_suppl.LBA1006 CrossRefGoogle Scholar
- 59.O’Leary B, Hrebien S, Morden JP, Beaney M, Fribbens C, Huang X, et al. Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer. Nat Commun [Internet]. Nature Publishing Group; 2018 [cited 2018 Mar 13];9:896. Available from: http://www.nature.com/articles/s41467-018-03215-x
- 60.Spoerke JM, Gendreau S, Walter K, Qiu J, Wilson TR, Savage H, et al. Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant. Nat Commun [Internet]. 2016;7:11579. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27174596.
- 61.Formisano L, Lu Y, Jansen V, Bauer J, Hanker A, Gonzalez Ericsson P, et al. Abstract GS6–05: Gain-of-function kinase library screen identifies FGFR1 amplification as a mechanism of resistance to antiestrogens and CDK4/6 inhibitors in ER+ breast cancer. Cancer Res [Internet]. 2018;78:GS6–05-GS6–05. Available from: https://doi.org/10.1158/1538-7445.SABCS17-GS6-05
- 62.Condorelli R, Spring L, O’Shaughnessy J, Lacroix L, Bailleux C, Scott V, et al. Polyclonal RB1 mutations and acquired resistance to CDK 4/6 inhibitors in patients with metastatic breast cancer. Ann Oncol [Internet]. 2018;29:640–5 Available from: https://academic.oup.com/annonc/article/29/3/640/4725051.CrossRefGoogle Scholar
- 63.•Hartmaier RJ, Trabucco SE, Priedigkeit N, Chung JH, Parachoniak CA, Vanden Borre P, et al. Recurrent hyperactive ESR1 fusion proteins in endocrine therapy resistant breast cancer. Ann Oncol [Internet]. 2018; Available from: https://doi.org/10.1093/annonc/mdy025/4817340. Proof of concept on the complexity of ESR1-driven treatment resistance.
- 64.Commissioner O of the. Press Announcements - FDA announces approval, CMS proposes coverage of first breakthrough-designated test to detect extensive number of cancer biomarkers. Office of the Commissioner; [cited 2019 Feb 16]; Available from: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm587273.htm
- 65.Turnbull C. Introducing whole-genome sequencing into routine cancer care: the genomics England 100 000 genomes project. Ann Oncol [Internet]. 2018;29:784–7 Available from: https://academic.oup.com/annonc/article/29/4/784/4860707.CrossRefGoogle Scholar
- 66.Lethimonnier F, Levy Y. Genomic medicine France 2025. Ann Oncol [Internet]. 2018;29:783–4 Available from: https://academic.oup.com/annonc/article/29/4/783/4817342.CrossRefGoogle Scholar
- 68.Kim S-B, Dent R, Im S-A, Espié M, Blau S, Tan AR, et al. Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol [Internet]. 2017;18:1360–72 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28800861.CrossRefGoogle Scholar
- 69.Ma CX, Bose R, Gao F, Freedman RA, Telli ML, Kimmick G, et al. Neratinib efficacy and circulating tumor DNA detection of HER2 mutations in HER2 nonamplified metastatic breast cancer. Clin Cancer Res [Internet]. 2017;23:5687–95. Available from: https://doi.org/10.1158/1078-0432.CCR-17-0900 CrossRefGoogle Scholar
- 71.Ross JS, Gay LM, Wang K, Ali SM, Chumsri S, Elvin JA, et al. Nonamplification ERBB2 genomic alterations in 5605 cases of recurrent and metastatic breast cancer: An emerging opportunity for anti-HER2 targeted therapies. Cancer [Internet]. 2016;122:2654–62. Available from: https://doi.org/10.1002/cncr.30102 CrossRefGoogle Scholar
- 72.Merker JD, Oxnard GR, Compton C, Diehn M, Hurley P, Lazar AJ, et al. Circulating tumor DNA analysis in patients with cancer: American Society of Clinical Oncology and College of American Pathologists Joint Review. J Clin Oncol [Internet]. 2018 [cited 2018 Mar 19];36:JCO.2017.76.867. Available from: https://doi.org/10.1200/JCO.2017.76.8671 CrossRefGoogle Scholar
- 73.Pelizzari G, Gerratana L, Basile D, Fanotto V, Bartoletti M, Liguori A, et al. Post-neoadjuvant strategies in breast cancer: From risk assessment to treatment escalation. Cancer Treat Rev [Internet]. Elsevier; 2019 [cited 2018 Nov 1];72:7–14. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0305737218301841 CrossRefGoogle Scholar
- 74.De Mattos-Arruda L, Weigelt B, Cortes J, Won HH, Ng CKY, Nuciforo P, et al. Capturing intra-tumor genetic heterogeneity by de novo mutation profiling of circulating cell-free tumor DNA: a proof-of-principle. Ann Oncol [Internet] 2014;25:1729–1735. Available from: https://doi.org/10.1093/annonc/mdu239 CrossRefGoogle Scholar
- 75.Arneth B. Update on the types and usage of liquid biopsies in the clinical setting: a systematic review. BMC Cancer [Internet]. 2018;18:527. Available from: https://doi.org/10.1186/s12885-018-4433-3
- 76.Gold B, Cankovic M, Furtado LV, Meier F, Gocke CD. Do circulating tumor cells, exosomes, and circulating tumor nucleic acids have clinical utility? J Mol Diagnostics [Internet]. 2015;17:209–24 Available from: https://linkinghub.elsevier.com/retrieve/pii/S1525157815000471.CrossRefGoogle Scholar