Towards Routine Implementation of Liquid Biopsies in Cancer Management: It Is Always Too Early, until Suddenly It Is Too Late

Maarten J IJzerman, Jasper de Boer, Arun Azad, Koen Degeling, Joel Geoghegan, Chelsee Hewitt, Frédéric Hollande, Belinda Lee, Yat Ho To, Richard W Tothill, Gavin Wright, Jeanne Tie, Sarah-Jane Dawson, Maarten J IJzerman, Jasper de Boer, Arun Azad, Koen Degeling, Joel Geoghegan, Chelsee Hewitt, Frédéric Hollande, Belinda Lee, Yat Ho To, Richard W Tothill, Gavin Wright, Jeanne Tie, Sarah-Jane Dawson

Abstract

Blood-based liquid biopsies are considered a new and promising diagnostic and monitoring tool for cancer. As liquid biopsies only require a blood draw, they are non-invasive, potentially more rapid and assumed to be a less costly alternative to genomic analysis of tissue biopsies. A multi-disciplinary workshop (n = 98 registrations) was organized to discuss routine implementation of liquid biopsies in cancer management. Real-time polls were used to engage with experts' about the current evidence of clinical utility and the barriers to implementation of liquid biopsies. Clinical, laboratory and health economics presentations were given to illustrate the opportunities and current levels of evidence, followed by three moderated break-out sessions to discuss applications. The workshop concluded that tumor-informed assays using next-generation sequencing (NGS) or PCR-based genotyping assays will most likely provide better clinical utility than tumor-agnostic assays, yet at a higher cost. For routine application, it will be essential to determine clinical utility, to define the minimum quality standards and performance of testing platforms and to ensure their use is integrated into current clinical workflows including how they complement tissue biopsies and imaging. Early health economic models may help identifying the most viable application of liquid biopsies. Alternative funding models for the translation of complex molecular diagnostics, such as liquid biopsies, may also be explored if clinical utility has been demonstrated and when their use is recommended in multi-disciplinary consensus guidelines.

Keywords: CTC; biomarkers; cancer; cancer surveillance; ctDNA; early detection; genomics; health economics; health services research; liquid biopsy; minimal residual disease.

Conflict of interest statement

S.-J.D. has received research funding to her institution from Roche-Genentech and Cancer Therapeutics CRC. She has been a member of advisory boards for AstraZeneca and Inivata. M.J.I. has received research funding to his institution from Illumina and has been a member of advisory boards for Illumina and RTI Health Solutions. A.A. received research funding as an investigator and to his institution from Astellas, Merck Serono, Astra Zeneca, Bristol Myers Squibb, Aptevo Therapeutics, Glaxo Smith Kline, Pfizer, MedImmune, SYNthorx, Bionomics, Sanofi Aventis, Novartis and Ipsen. Other authors declare no conflicts of interest. None of the listed funders had a role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Example of an evidence slider with which the translational research phase was determined. Each workshop participant could vote once (green dots) following a discussion about this case in the break-out sessions. The individual votes are used to construct density plots.
Figure 2
Figure 2
Pre-workshop question asking which application will likely have the most impact and for which application the most scientific progress has been made.
Figure 3
Figure 3
Results of ranking 5 statements related to clinical use of ctDNA.
Figure 4
Figure 4
Ranking of statements relevant for health economic modeling of liquid biopsies.
Figure 5
Figure 5
Density plots presenting the translational stage of the 4 ctDNA applications.

References

    1. Ashworth T.R. A Case of Cancer in Which Cells Similar to Those in the Tumors Were Seen in the Blood after Death. Australas. Med. J. 1869;14:146–149.
    1. Allard W.J., Matera J., Miller M.C., Repollet M., Connelly M.C., Rao C., Tibbe A.G.J., Uhr J.W., Terstappen L.W.M.M. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin. Cancer Res. Am. Assoc. Cancer Res. 2004;10:6897–6904. doi: 10.1158/1078-0432.CCR-04-0378.
    1. De Bono J.S., Scher H.I., Montgomery R.B., Parker C., Miller M.C., Tissing H., Doyle G.V., Terstappen L.W.W.M., Pienta K.J., Raghavan D. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin. Cancer Res. Am. Assoc. Cancer Res. 2008;14:6302–6309. doi: 10.1158/1078-0432.CCR-08-0872.
    1. Cristofanilli M., Hayes D.F., Budd G.T., Ellis M.J., Stopeck A., Reuben J.M., Doyle G.V., Matera J., Allard W.J., Miller M.C., et al. Circulating tumor cells: A novel prognostic factor for newly diagnosed metastatic breast cancer. J. Clin. Oncol. 2005;23:1420–1430. doi: 10.1200/JCO.2005.08.140.
    1. Cohen S.J., Punt C.J.A., Iannotti N., Saidman B.H., Sabbath K.D., Gabrail N.Y., Picus J., Morse M., Mitchell E., Miller M.C., et al. Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J. Clin. Oncol. 2008;26:3213–3221. doi: 10.1200/JCO.2007.15.8923.
    1. Miller M.C., Doyle G.V., Terstappen L.W.M.M. Significance of Circulating Tumor Cells Detected by the CellSearch System in Patients with Metastatic Breast Colorectal and Prostate Cancer. J. Oncol. 2010;2010:617421. doi: 10.1155/2010/617421.
    1. Krebs M.G., Renehan A.G., Backen A., Gollins S., Chau I., Hasan J., Valle J.W., Morris K., Beech J., Ashcroft L., et al. Circulating Tumor Cell Enumeration in a Phase II Trial of a Four-Drug Regimen in Advanced Colorectal Cancer. Clin. Colorectal Cancer. 2015;14:115–122. doi: 10.1016/j.clcc.2014.12.006.
    1. Goldkorn A., Ely B., Quinn D.I., Tangen C.M., Fink L.M., Xu T., Twardowski P., van Veldhuizen P.J., Agarwal N., Carducci M.A., et al. Circulating Tumor Cell Counts Are Prognostic of Overall Survival in SWOG S0421: A Phase III Trial of Docetaxel With or Without Atrasentan for Metastatic Castration-Resistant Prostate Cancer. J. Clin. Oncol. 2014;32:1136–1142. doi: 10.1200/JCO.2013.51.7417.
    1. Smerage J.B., Barlow W.E., Hortobagyi G.N., Winer E.P., Jones B.L., Srkalovic G., Tejwani S., Schott A.F., O’Rourke M.A., Lew D.L., et al. Circulating Tumor Cells and Response to Chemotherapy in Metastatic Breast Cancer: SWOG S0500. J. Clin. Oncol. 2014;32:3483–3490. doi: 10.1200/JCO.2014.56.2561.
    1. Bidard F.C., Jacot W., Kiavue N., Dureau S., Kadi A., Brain E., Bachelot T., Bourgeois H., Gonçalves A., Ladoire S., et al. Efficacy of Circulating Tumor Cell Count–Driven vs Clinician-Driven First-line Therapy Choice in Hormone Receptor–Positive, ERBB2-Negative Metastatic Breast Cancer. JAMA Oncol. 2020:e205660. doi: 10.1001/jamaoncol.2020.5660.
    1. Aranda E., Viéitez J.M., España A.G., Calle S.G., Salvia A.S., Graña B., Garcia-Alfonso P., Rivera F., Aldana G.A.Q., Zoilo J.J.R., et al. FOLFOXIRI plus bevacizumab versus FOLFOX plus bevacizumab for patients with metastatic colorectal cancer and ≥3 circulating tumour cells: The randomised phase III VISNÚ-1 trial. ESMO Open. 2020;5:e000944. doi: 10.1136/esmoopen-2020-000944.
    1. Lorente D., Olmos D., Mateo J., Bianchini D., Seed G., Fleisher M., Danila D.C., Flohr P., Crespo M., Figueiredo I., et al. Decline in Circulating Tumor Cell Count and Treatment Outcome in Advanced Prostate Cancer. Eur. Urol. 2016;70:985–992. doi: 10.1016/j.eururo.2016.05.023.
    1. Sumanasuriya S., Omlin A., Armstron A., Attard G., Chi K.N., Bevan C.L., Shibakawa A., Jzerman M.J.I., Laere B., Lolkema M., et al. Consensus Statement on Circulating Biomarkers for Advanced Prostate Cancer. Eur. Urol. Oncol. 2018;1:151–159. doi: 10.1016/j.euo.2018.02.009.
    1. Huang W.L., Chen Y.L., Yang S.C., Ho C.L., Wei F., Wong D.T., Su W.C., Lin C.C. Liquid biopsy genotyping in lung cancer: Ready for clinical utility? Oncotarget. 2017;8:18590–18608. doi: 10.18632/oncotarget.14613.
    1. Cabel L., Proudhon C., Gortais H., Loirat D., Coussy F., Pierga J.Y., Bidard F.C. Circulating tumor cells: Clinical validity and utility. Int. J. Clin. Oncol. 2017;22:421–430. doi: 10.1007/s10147-017-1105-2.
    1. Siravegna G., Marsoni S., Siena S., Bardelli A. Integrating liquid biopsies into the management of cancer. Nat. Rev. Clin. Oncol. 2017;14:531–548. doi: 10.1038/nrclinonc.2017.14.
    1. Elazezy M., Joosse S.A. Techniques of using circulating tumor DNA as a liquid biopsy component in cancer management. Comput. Struct. Biotechnol. J. 2018;16:370–378. doi: 10.1016/j.csbj.2018.10.002.
    1. Heitzer E., Haque I.S., Roberts C.E.S., Speicher M.R. Current and future perspectives of liquid biopsies in genomics-driven oncology. Nat. Rev. Genet. 2019;20:71–88. doi: 10.1038/s41576-018-0071-5.
    1. Devonshire A.S., Whale A.S., Gutteridge A., Jones G., Cowen S., Foy C.A., Hugget J.F. Towards standardisation of cell-free DNA measurement in plasma: Controls for extraction efficiency, fragment size bias and quantification. Anal. Bioanal. Chem. 2014;406:6499–6512. doi: 10.1007/s00216-014-7835-3.
    1. Deans Z.C., Butler R., Cheetham M., Dequeker E.M.C., Fairley J.A., Fenizia F., Hall J.A., Keppens C., Normanno N., Schuuring E., et al. IQN path ASBL report from the first European cfDNA consensus meeting: Expert opinion on the minimal requirements for clinical ctDNA testing. Virchows Arch. 2019;474:681–689. doi: 10.1007/s00428-019-02571-3.
    1. Bettegowda C., Sausen M., Leary R.J., Kinde I., Wang Y., Agrawal N., Bartlett B.R., Wang H., Luber B., Alani R.M., et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci. Transl. Med. 2014;6:224ra24. doi: 10.1126/scitranslmed.3007094.
    1. Cohen J.D., Li L., Wang Y., Thoburn C., Afsari B., Danilova L., Douville C., Javed A.A., Wong F., Mattox A., et al. Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science. 2018;359:926–930. doi: 10.1126/science.aar3247.
    1. Liu M.C., Oxnard G.R., Klein E.A., Swanton C., Seiden M.V., Cummings S.R., Absalan F., Alexander G., Allen B., Aminiet H., et al. Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA. Ann. Oncol. 2020;31:745–759. doi: 10.1016/j.annonc.2020.02.011.
    1. Chen X., Gole J., Gore A., He Q., Lu M., Min J., Yuan Z., Yang X., Jiang Y., Zhang T., et al. Non-invasive early detection of cancer four years before conventional diagnosis using a blood test. Nat. Commun. 2020;11:3475. doi: 10.1038/s41467-020-17316-z.
    1. Merker J.D., Oxnard G.R., Compton C., Diehn M., Hurley P., Lazar A.J., Lindeman N., Lockwood C.M., Rai A.J., Schilsky R.L., 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. Am. Soc. Clin. Oncol. 2018;36:1631–1641. doi: 10.1200/JCO.2017.76.8671.
    1. Van Delft F., Koffijberg H., Retèl V., Heuvel M.V.D., IJzerman M.J. The Validity and Predictive Value of Blood-Based Biomarkers in Prediction of Response in the Treatment of Metastatic Non-Small Cell Lung Cancer: A Systematic Review. Cancers. 2020;12:1120. doi: 10.3390/cancers12051120.
    1. Turner N.C., Kingston B., Kilburn L.S., Kernaghan S., Wardley A.M., Macpherson I.R., Baird R.D., Roylance R., Stephens P., Oikonomidou O., et al. Circulating tumour DNA analysis to direct therapy in advanced breast cancer (plasmaMATCH): A multicentre, multicohort, phase 2a, platform trial. Lancet Oncol. 2020;21:1296–1308. doi: 10.1016/S1470-2045(20)30444-7.
    1. Morelli M.P., Overman M.J., Dasari A., Kazmi S.M.A., Mazard T., Vilar E., Morris V.K., Lee M.S., Herron D., Eng C., et al. Characterizing the patterns of clonal selection in circulating tumor DNA from patients with colorectal cancer refractory to anti-EGFR treatment. Ann. Oncol. 2015;26:731–736. doi: 10.1093/annonc/mdv005.
    1. Parseghian C.M., Loree J.M., Morris V.K., Liu X., Clifton K.K., Napolitano S., Henry J.T., Pereira A.A., Vilar E., Johnson B., et al. Anti-EGFR-resistant clones decay exponentially after progression: Implications for anti-EGFR re-challenge. Ann. Oncol. 2019;30:243–249. doi: 10.1093/annonc/mdy509.
    1. Abbosh C., Birkbak N.J., Wilson G.A., Jamal-Hanjani M., Constantin T., Salari R., le Quesne J., Moore D.A., Veeriah S., Rosenthal R., et al. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature. 2017;545:446–451. doi: 10.1038/nature22364.
    1. Tie J., Cohen J.D., Wang Y., Christie M., Simons K., Lee M., Wong R., Kosmider S., Ananda S., McKendrick J., et al. Circulating Tumor DNA Analyses as Markers of Recurrence Risk and Benefit of Adjuvant Therapy for Stage III Colon Cancer. JAMA Oncol. 2019;5:1710–1718. doi: 10.1001/jamaoncol.2019.3616.
    1. Lee B., Lipton L., Cohen J., Tie J., Javed A.A., Li L., Goldstein D., Burge M., Cooray P., Nagrial A., et al. Circulating tumor DNA as a potential marker of adjuvant chemotherapy benefit following surgery for localized pancreatic cancer. Ann. Oncol. 2019;30:1472–1478. doi: 10.1093/annonc/mdz200.
    1. Murillas I.G., Schiavon G., Weigelt B., Ng C., Hrebien S., Cutts R.J., Cheang M., Osin P., Nerurkar A., Kozarewa I., et al. Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Sci. Transl. Med. 2015;7:302ra133.
    1. Christensen E., Demtröder K.B., Sethi H., Shchegrova S., Salari R., Nordentoft I., Wu H.T., Knudsen M., Lamy P., Lindskrog S.V., et al. Early Detection of Metastatic Relapse and Monitoring of Therapeutic Efficacy by Ultra-Deep Sequencing of Plasma Cell-Free DNA in Patients With Urothelial Bladder Carcinoma. J. Clin. Oncol. 2019;37:1547–1557. doi: 10.1200/JCO.18.02052.
    1. Lee J.H., Saw R.P., Thompson J.F., Lo S., Spillane A.J., Shannon K.F., Stretch J.R., Howle J., Menzies A.M., Carlino M.S., et al. Pre-operative ctDNA predicts survival in high-risk stage III cutaneous melanoma patients. Ann. Oncol. 2019;30:815–822. doi: 10.1093/annonc/mdz075.
    1. Lee J.H., Saw R.P., Thompson J.F., Lo S., Spillane A.J., Shannon K.F., Stretch J.R., Howle J., Menzies A.M., Carlino M.S., et al. Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer. Sci. Transl. Med. 2016;8:346ra92.
    1. Tie J., Cohen J.D., Wang Y., Li L., Christie M., Simons K., Elsaleh H., Kosmider S., Wong R., Yip D., et al. Serial circulating tumour DNA analysis during multimodality treatment of locally advanced rectal cancer: A prospective biomarker study. Gut. 2019;68:663–671. doi: 10.1136/gutjnl-2017-315852.
    1. Tan L., Sandhu S., Lee R.J., Li J., Callahan J., Ftouni S., Dhomen N., Middlehurst P., Wallace A., Raleigh J., et al. Prediction and monitoring of relapse in stage III melanoma using circulating tumor DNA. Ann. Oncol. 2019;30:804–814. doi: 10.1093/annonc/mdz048.
    1. Berghuis A.M.S., Koffijberg H., Prakash J., Terstappen L.W.M.M., IJzerman M.J. Detecting Blood-Based Biomarkers in Metastatic Breast Cancer: A Systematic Review of Their Current Status and Clinical Utility. Int. J. Mol. Sci. 2017;18:363. doi: 10.3390/ijms18020363.
    1. IJzerman M.J., Berghuis A.M.S., de Bono J.S., Terstappen L.W.M.M. Health economic impact of liquid biopsies in cancer management. Expert Rev. Pharm. Outcomes Res. 2018;18:593–599. doi: 10.1080/14737167.2018.1505505.
    1. Vessies D., Greuter M., van Rooijen K. Performance of four platforms for KRAS mutation detection in plasma cell-free DNA: ddPCR, Idylla, COBAS z480 and BEAMing. Nat. Com. 2020;10:13. doi: 10.1038/s41598-020-64822-7.
    1. National Institute for Health and Care Excellence (NICE) Plasma EGFR Mutation Tests for Adults with Locally Advanced or Metastatic Non-Small-Cell Lung Cancer. Natl. Inst. Health Care Excell. 2018, Medtech Innovation Briefing. [(accessed on 7 January 2021)]; Available online: .
    1. Calderón D.S., Pedraza A., Urrego C.M., Mejía A.M., Páez A.L.M., Perdomo S. Analysis of the Cost-Effectiveness of Liquid Biopsy to Determine Treatment Change in Patients with Her2-Positive Advanced Breast Cancer in Colombia. Clin. Outcomes Res. 2020;12:115–122. doi: 10.2147/CEOR.S220726.
    1. Degeling K., Schivo S., Mehra N., Koffijberg H., Langerak R., de Bono J.S., Jzerman M.J.I. Comparison of Timed Automata with Discrete Event Simulation for Modeling of Biomarker-Based Treatment Decisions: An Illustration for Metastatic Castration-Resistant Prostate Cancer. Value Health. 2017;20:1411–1419. doi: 10.1016/j.jval.2017.05.024.
    1. Kapoor R., So J.B.Y., Zhu F., Too H.-P., Yeoh K.-G., Yoong J.S.-Y. Evaluating the Use of microRNA Blood Tests for Gastric Cancer Screening in a Stratified Population-Level Screening Program: An Early Model-Based Cost-Effectiveness Analysis. Value Health. 2020;23:1171–1179. doi: 10.1016/j.jval.2020.04.1829.
    1. Douglas M.P., Gray S.W., Phillips K.A. Private Payer and Medicare Coverage for Circulating Tumor DNA Testing: A Historical Analysis of Coverage Policies From 2015 to 2019. J. Natl. Compr. Cancer Netw. 2020;18:866–872. doi: 10.6004/jnccn.2020.7542.
    1. Wan J.C.M., Massie C., Corbacho J.G., Mouliere F., Brenton J.D., Caldas C., Pacey S., Baird R., Rosenfeld N. Liquid biopsies come of age: Towards implementation of circulating tumour DNA. Nat. Rev. Cancer. 2017;17:223–238. doi: 10.1038/nrc.2017.7.
    1. Cescon D.W., Bratman S.V., Chan S.M., Siu L.L. Circulating tumor DNA and liquid biopsy in oncology. Nat. Cancer. 2020;1:276–290. doi: 10.1038/s43018-020-0043-5.
    1. Leighl N.B., Rekhtman N., Biermann W.A., Huang J., Kenudson M.M., Ramalingam S.S., West H., Whitlock S., Somerfield M.R. Molecular testing for selection of patients with lung cancer for epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors. J. Clin. Oncol. 2014;32:3673–3679. doi: 10.1200/JCO.2014.57.3055.
    1. Guibert N., Pradines A., Favre G., Mazières J. Current and future applications of liquid biopsy in nonsmall cell lung cancer from early to advanced stages. Eur. Respir. Rev. 2020;29:190052. doi: 10.1183/16000617.0052-2019.
    1. Janni W.J., Rack B., Terstappen L.W.M.M., Pierga J.Y., Taran F.A., Fehm T., Hall C., de Groot M.R., Bidard F.C., Friedl T.W.P., et al. Pooled Analysis of the Prognostic Relevance of Circulating Tumor Cells in Primary Breast Cancer. Clin. Cancer Res. 2016;22:2583–2593. doi: 10.1158/1078-0432.CCR-15-1603.
    1. Yoshinami T., Kagara N., Motooka D., Nakamura S., Miyake T., Tanei T., Naoi Y., Shimoda M., Shimazu K., Kim S.J., et al. Detection of ct DNA with Personalized Molecular Barcode NGS and Its Clinical Significance in Patients with Early Breast Cancer. Transl. Oncol. 2020;13:100787. doi: 10.1016/j.tranon.2020.100787.
    1. Pantel K., Panabières C.A. Liquid biopsy and minimal residual disease-latest advances and implications for cure. Nat. Rev. Clin. Oncol. 2019;16:409–424. doi: 10.1038/s41571-019-0187-3.
    1. IJzerman M.J., Koffijberg H., Fenwick E., Krahn M. Emerging Use of Early Health Technology Assessment in Medical Product Development: A Scoping Review of the Literature. Pharmacoeconomics. 2017;35:727–740. doi: 10.1007/s40273-017-0509-1.
    1. Towse A., Garrison L.P. Economic incentives for evidence generation: Promoting an efficient path to personalized medicine. Value Health. 2013;16(Suppl. 6):S39–S43. doi: 10.1016/j.jval.2013.06.003.
    1. Ramsey S.D., Sullivan S.D. A new model for reimbursing genome-based cancer care. Oncologist. 2014;19:1–4. doi: 10.1634/theoncologist.2013-0392.
    1. Bernabé R., Hickson N., Wallace A., Blackhall F.H. What do we need to make circulating tumour DNA (ctDNA) a routine diagnostic test in lung cancer? Eur. J. Cancer. 2017;81:66–73. doi: 10.1016/j.ejca.2017.04.022.
    1. Faulkner E., Holtorf A.P., Walton S., Liu C.Y., Lin H., Biltaj E., Brixner D., Barr C., Oberg J., Shandhu G., et al. Being Precise About Precision Medicine: What Should Value Frameworks Incorporate to Address Precision Medicine? A Report of the Personalized Precision Medicine Special Interest Group. Value Health. 2020;23:529–539. doi: 10.1016/j.jval.2019.11.010.
    1. Cristofanilli M., Pierga J.Y., Reuben J., Rademaker A., Davis A.A., Peeters D.J., Fehm T., Nolé F., Criado R.G., Mavroudis D., et al. The clinical use of circulating tumor cells (CTCs) enumeration for staging of metastatic breast cancer (MBC): International expert consensus paper. Crit. Rev. Oncol. Hematol. 2019;134:39–45. doi: 10.1016/j.critrevonc.2018.12.004.
    1. Dasari A., Morris V.K., Allegra C.J., Atreya C., Benson A.B., III, Boland P., Chung K., Copur M.S., Corcoran R.B., Deming D.A., et al. ct DNA applications and integration in colorectal cancer: An NCI Colon and Rectal–Anal Task Forces whitepaper. Nat. Rev. Clin. Oncol. 2020;17:757–770. doi: 10.1038/s41571-020-0392-0.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir