liquid biopsies - uclmontgodinne.be · 5 why? comparison to gold standard : tumor biopsy o...
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o Peter Vuylsteke o Oncologie médicale o CHU UCL Namur , Ste-Elisabeth
Liquid Biopsies
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o What
o Why
o When and How
Outline
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What?
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What?
o ctDNA (short DNA fragments of dying cancer cells)
o Circulating microRNA
o CTC (xenografts)
o Microvesicles
o Proteins and metabolites,…
…(can be found in any body-fluid)
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Why?
Comparison to gold standard : Tumor biopsy o Accessibility >< « liquid »
o Sometimes no tumor…
o Repeat biopsy : « please don’t do it again, doc »
o Heterogeneinity
o Processing time
o Paraffin blocs (if retrospective),...
cfDNA • Used routinely in pregnancy: detect fetal DNA
• Cancer: ctDNA: not as « easy » as fetal DNA
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When and How
o Screening: Detect cancer « earlier »
o Post-treatment: residual ?disease recurrence ?
o Advanced disease: treatment selection and monitoring
o Refractory disease: mechanism of resistance
1/Screening Detect tumor before the tumor is « visible »
• Conclusion;: « These data suggest circulating miRNAs have potential to develop a non-invasive diagnostic test for ovarian cancer »
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Benign disease
Borderline tumors
non-HGSOC invasive carcinomas
HGSOC invasive carcinomas
Stable genome (2n)
Unstable genome
Vanderstichele et al. Clin Cancer Res 2017
Masse adnexielle: Bénin ou non? cfDNA: Copy Number Variation
cfDNA RMI CA-125
high specificity:cfDNA is 2-5 times higher
2x
5x
Useful for presurgical characterization
Benign versus HGSOC
Vanderstichele et al. Clin Cancer Res 2017
cfDNA always specific? «normal» cells can also shed mutated cfDNA
• Why? • Clonal Mosaicism.. • Aging (WBC)
• Eg SCLC: tp 53 mutation
cfDNA screening in general population for cancers
without a specific mutation = not mature
– Whom to screen then? Patients at risk:
2/Detect residual disease and screening for recurrence
• Sequence the tumor first! Personalised ctDNA assay looking for the mutations found in tumor.
prognostic
Colorectal cancer st II
Pancreatic cancer Breast cancer
CEA Tumor marker
ctDNA
ctDNA ctDNA
Sausen M et al.
Nat Commun 2015
Garcia-Murillas I et
al.
Sci Transl Med 2015
Tie et al.
Sci Transl Med 2016
Can you do something about it? Trials needed:
• Colon Ca st II: adj chemotherapy helps?
• cTRAK TN (UK) – High risk TN breast Ca, post adjuvant setting
• If ctDNA becomes pos in first year – Random : Pembro vs observation
• Treat CTC trial (EORTC)
ctDNA: EARLY marker of Recurrence
Ovarian
Pereira E et al. Plos One 2015
Lead time for ctDNA
6 months over CA-125
7 months over symptoms
3/ Relapse
Finetune your Therapy
–Choose best treatment
–Monitor response
Choose the best treatment upfront
• Trials: ctDNA sequencing in metastatic setting. – Treatment according to mutation(s) found
– Challenges: • All tumors? (only « targetable» tumors?)
• Treatment available ?(off-label? Precision-trial BSMO)
• Better than standard approach? Randomised..?
– AURORA
Monitor: ctDNA, early marker of response
Parkinson CA et al. Plos Medicine 2016
Ovarian cancer: >60% decrease in ctDNA (p53)
after 1 cycle chemo
= predictor of longer time-to-progression
(D CA125 was no significant predictor)
USEFUL in the CLINIC? We treat if there is response, even if minimal response…
4/Resistance • Often a sign of subclonal development.
Resistance: ctDNA clinical use (FDA)
• Lung Cancer with EGFR mutation
– Gefitinib/ Erlotinib: EGFR TKI
– Monitor cfDNA for EGFR T790: start Osimertinib
• Breast cancer?
TR
• Breast
• Ovarian: Resistance to PARP-inhibitors ?
Norquist et al. JCO 2011
45 recurrent BRCA-mutated relapsed ovarian cancers
13/45 (29%) had secondary rev mutation
12/13 (92%) were platinum-resistant at recurrence
BRCA reversion mutations: platinum/PARP-Inh resistance
Clinically usefull
• Whether to Start/Stop Parp-Inhibitor
• At 5000 euro/mth of treatment cost
– A 500 euro ctDNA monitoring may be worth it.
• Etude CLIO
Conclusion
• Liquid biopsies: part of our TR research tools
• They are getting faster…and cheaper…
• They will help us to help our patients better: find the right treatment, for the right tumor, at the right moment.
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THANK YOU
