Round Table: Tissue Biopsy versus Liquid Biopsy. César A. Rodríguez Hospital Universitario de Salamanca-IBSAL

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1 Round Table: Tissue Biopsy versus Liquid Biopsy César A. Rodríguez Hospital Universitario de Salamanca-IBSAL

2 Introduction Classic Advantages of liquid biopsy collection over standard biopsy Standard biopsy Invasive Not easy to obtain from some organs Expensive Long processing time Sometimes high failure rate (Tumor not identified / quantity not sufficient) Serial biopsies are difficult to tolerate throughout the disease process. Sample remain stable when processed for long periods of time. The evaluation of tumor heterogeneity limited to that of the analyzed biopsy Not easy to follow treatment response Liquid biopsy Minimally Invasive Easy to obtain from patient blood Less Expensive Short processing time Low failure rate Serial biopsies can be tolerated throughout the disease process. Sample can remain stable for long periods of time under exvivo conditions Can capture tumor heterogeneity Easy to follow treatment response

3 Introduction The molecular profile of tumours evolves dynamically over time. The genetic map of individual cancers is heterogeneous: In a single patient, metastatic lesions can be molecularly divergent. Therapeutic stress on tumour cells, (i.e. targeted drugs), can dynamically modify the genomic landscape of tumours. Murtaza, M. et al. Nat. Commun. 6, 8760 (2015).

4 Applications of Liquid Biopsy during the course of the disease.

5 Liquid Biopsy and Early Detection of Cancer

6 Liquid Biopsy and Early Detection of Cancer

7 Prognosis & Residual Disease

8 Prognosis & Residual Disease

9 Prognosis & Residual Disease Tie et al. Sci Transl Med 2016

10 Monitoring Response

11 Mutant Allele Fraction (%) Mutant Allele Fraction (%) Mutant Allele Fraction (%) Mutant Allele Fraction (%) Mutant Allele Fraction (%) Mutant Allele Fraction (%) Monitoring Response Longitudinal monitoring during the course of targeted therapy Figure 1 Primary breast tumour Primary Tumor 100 Plasma 2 AKT inhibitor 100 Plasma 4 Mutant Allele Fraction % CDKN2A p.s12* AKT1 p.e17k TP53 p.k132n JAK3 p.t21m TSC1 p.s1046c NF1 p.v2420fs CDH1 p.159_171p MLL3 p.g292e 0 CTNNB1 p.a522g PIK3C2G p.k978n GATA1 p.k315n EPHB1 p.i332m ESR1 p.e380q PAK7 p.e494* MAP2K2 p.e207q FLT4 p.r282q Genes Paclitaxel-based Anthracycline-based Capecitabine-base Baseline CDKN2A p.s12* AKT1 p.e17k TP53 p.k132n JAK3 p.t21m TSC1 p.s1046c NF1 p.v2420fs CDH1 p.159_171p MLL3 p.g292e 0 CTNNB1 p.a522g PIK3C2G p.k978n GATA1 p.k315n EPHB1 p.i332m ESR1 p.e380q PAK7 p.e494* MAP2K2 p.e207q FLT4 p.r282q 6 months CDKN2A p.s12* AKT1 p.e17k TP53 p.k132n JAK3 p.t21m TSC1 p.s1046c NF1 p.v2420fs CDH1 p.159_171p MLL3 p.g292e 0 CTNNB1 p.a522g PIK3C2G p.k978n GATA1 p.k315n EPHB1 p.i332m ESR1 p.e380q PAK7 p.e494* MAP2K2 p.e207q FLT4 p.r282q Liver Metastasis 100 Liver Metastasis Mutant Allele Fraction % CDKN2A p.s12* AKT1 p.e17k TP53 p.k132n JAK3 p.t21m TSC1 p.s1046c NF1 p.v2420fs CDH1 p.159_171p MLL3 p.g292e 0 CTNNB1 p.a522g PIK3C2G p.k978n GATA1 p.k315n EPHB1 p.i332m ESR1 p.e380q PAK7 p.e494* MAP2K2 p.e207q FLT4 p.r282q Genes MAF > 50% MAF 20-50% CDKN2A p.s12* AKT1 p.e17k TP53 p.k132n JAK3 p.t21m TSC1 p.s1046c NF1 p.v2420fs CDH1 p.159_171p MLL3 p.g292e 0 Plasma 1 CTNNB1 p.a522g PIK3C2G p.k978n GATA1 p.k315n EPHB1 p.i332m ESR1 p.e380q PAK7 p.e494* MAP2K2 p.e207q FLT4 p.r282q 2 months CDKN2A p.s12* AKT1 p.e17k TP53 p.k132n JAK3 p.t21m TSC1 p.s1046c NF1 p.v2420fs CDH1 p.159_171p MLL3 p.g292e 0 Plasma 3 CTNNB1 p.a522g PIK3C2G p.k978n GATA1 p.k315n EPHB1 p.i332m ESR1 p.e380q PAK7 p.e494* MAP2K2 p.e207q FLT4 p.r282q Disease progression MAF 5-20% MAF < 5% MAF: Mutant Allele Fraction De Mattos-Arruda Annals Oncol 2014

12 Monitoring Clonal Evolution & Treatment Decisions Monitoring Clonal Evolution in Colorectal Cancer with Liquid Biopsy Siravegna G, et al. Nature Rev Clin Oncol 2017

13 Monitoring Clonal Evolution & Treatment Decisions Fribbens et al JCO, 2015

14 Monitoring Clonal Evolution & Treatment Decisions Wan JCM et al Nat Rev Cancer 2017 EGFR T790M mutation in NSCLC High concordance but faster detection in ctdna Sacher et al JAMAOncol 2016

15 Conclusion

16 Limitations and Disadvantages of Liquid Biopsy Lack of standard and convenient techniques Test variability and assay sensitivity and specificity Lack of consensus in technical approaches of choice Absence of information concerning histology or proliferation index Absence of information concerning tumor microenviroment Difficulty in sistematically performing immunocytochemistry and in situ hybridation (CTCs) Potentially miss biomarkers expressed in the tumor Finally, although many studies have been performed to prove the clinical utility, most were retrospective, so more rigorous studies are required to validate the substantial potential of liquid biopsy. + Hofman P, et al. Virchows Archiv. 2016;469: Zhang W, et al. Cell Physiol Biochem 2017; 41:

17 Conclusion Many real and potential advantages Present Limitations and Challenges Undoubted Promising (and immediate) Future