The combined analysis of solid and liquid biopsies provides additional clinical information to improve patient care

Abstract

Aim: To investigate if the genetic information provided by sequencing of both solid and liquid biopsies can shed light on tumor heterogeneity, and to understand the clinical usefulness of adding blood profiling to standard tissue analysis in cancer care.

Methods: Data from 351 patients with stage IV solid tumors for whom molecular profiling of their solid and liquid biopsies was available were studied, with a focus on the discrepant molecular information found between tissue and blood samples.

Results: In 86% of patients, solid and liquid biopsies provided different molecular information. Discrepant gene mutations with a functional impact on the corresponding protein were studied in detail. In 97% of cases, these additional mutations provided clinical value, mainly predicting sensitivity or resistance to targeted therapies. Specifically, 42% of the mutations found only in the liquid biopsy were directly predictive of approved therapies (80% targeted therapies), while 54% were inclusion criteria for molecularly-matched trials.

Conclusion: This study suggests that the addition of blood profiling should be considered in routine clinical oncology, especially for patients with metastatic disease where integrated analysis of solid and liquid biopsies provides a more complete characterization of tumor heterogeneity and provides valuable clinical information for patient treatment.

Keywords

Molecular profiling / solid tumor / liquid biopsy / solid biopsy / tumor heterogeneity / next-generation sequencing / precision medicine / targeted therapies

References

[1] La Thangue NB.Predictive biomarkers: a paradigm shift towards personalized cancer medicine..Nat Rev Clin Oncol2011;8:587-96

[2] Jackson SE.Personalised cancer medicine..Int J Cancer2015;137:262-6

[3] Zahreddine H.Mechanisms and insights into drug resistance in cancer..Front Pharmacol2013;4:1-8 PMCID:PMC3596793

[4] Seoane J.The challenge of intratumour heterogeneity in precision medicine..J Intern Med2014;276:41-51

[5] Junttila MR.Influence of tumour micro-environment heterogeneity on therapeutic response..Nature2013;501:346-54

[6] Turner NC.Genetic heterogeneity and cancer drug resistance..Lancet Oncol2012;13:e178-85

[7] Yi X,Guan Y,Yang L.The feasibility of using mutation detection in ctDNA to assess tumor dynamics..Int J Cancer2017;140:2642-7 PMCID:PMC5434851

[8] Diaz LJ.Liquid biopsies: genotyping circulating tumor DNA..J Clin Oncol2014;32:579-86 PMCID:PMC4820760

[9] Wan JCM,Garcia-Corbacho J,Brenton JD,Pacey S,Rosenfeld N.Liquid biopsies come of age: towards implementation of circulating tumour DNA..Nat Rev Cancer2017;17:223-38

[10] Clatot F,Di Fiore F.ESR1 mutations in breast cancer..Aging (Albany NY)2017;9:3-4 PMCID:PMC5310651

[11] Bronte G,Castiglia M,Passiglia F,Cicero G,Peeters M,Fanale D,Russo A.New findings on primary and acquired resistance to anti-EGFR therapy in metastatic colorectal cancer: do all roads lead to RAS?.Oncotarget2015;6:24780-96 PMCID:PMC4694794

[12] Therkildsen C,Henrichsen-Schnack T,Nilbert M.The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer: a systematic review and meta-analysis..Acta Oncol2014;53:852-64

[13] Liegl B,Le C,Demetri GD,Fletcher CD,Fletcher JA.Heterogeneity of kinase inhibitor resistance mechanisms in GIST..J Pathol2008;216:64-74 PMCID:PMC2693040

[14] Arcila ME,Chaft JE,Lau C,Zakowski MF,Ladanyi M.EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics..Mol Cancer Ther2013;12:220-9 PMCID:PMC3714231

[15] Diamond EL,Haroche J,Ma J,Wang Z,Kim E,Lee SC,Micol JB,Walsh MP,Dolgalev I,Heguy A,Nakitandwe J,Dalton JD,Estrada-Veras J,Gahl WA,Miller VA,Ali SM,Fasan O,Héritier S,Solit DB,Baselga J,Taylor BS,Amoura Z,Emile JF,Gruber TA.Diverse and targetable kinase alterations drive histiocytic neoplasms..Cancer Discov2016;6:154-65 PMCID:PMC4744547

[16] Bettegowda C,Leary RJ,Wang Y,Bartlett BR,Luber B,Antonarakis ES,Bardelli A,Cameron JL,Fecher LA,Gibbs P,Giuntoli RL,Hogarty MD,Hong SM,Juhl HH,Siravegna G,Lauricella C,Lipson EJ,Netto GJ,Olivi A,Riggins GJ,Schmidt K,Oba-Shinjo SM,Theodorescu D,Harkins TT,Wang TL,Wolfgang CL,Xing D,Wu J,Schmidt CM,Velculescu VE,Vogelstein B,Diaz LAJr.Detection of circulating tumor DNA in early- and late-stage human malignancies..Sci Transl Med2014;6:1-11 PMCID:PMC4017867

[17] Welch DR.Tumor heterogeneity - a 'contemporary concept' founded on historical insights and predictions..Cancer Res2016;76:4-6 PMCID:PMC4773023

[18] González S,Beer P.Immuno-oncology from the perspective of somatic evolution..Semin Cancer Biol2017;

[19] Kidess E.Circulating tumor cells versus tumor-derived cell- free DNA: rivals or partners in cancer care in the era of single-cell analysis?.Genome Med2013;5:1-4 PMCID:PMC3979136

[20] Bieging K,Attardi L.Unravelling mechanisms of p53-mediated tumour suppression..Nat Rev Cancer2014;14:359-70 PMCID:PMC4049238

[21] Rivlin N,Oren M.Mutations in the p53 tumor suppressor gene: important milestones at the various steps of tumorigenesis..Genes Cancer2011;2:466-74 PMCID:PMC3135636

[22] Samuels Y.Oncogenic mutations of PIK3CA in human cancers..Curr Top Microbiol Immunol2010;347:21-41

[23] Karakas B,Park BH.Mutation of the PIK3CA oncogene in human cancers..Br J Cancer2006;94:455-9 PMCID:PMC2361173