Liquid biopsy: ready for clinical practice?
Transcript of Liquid biopsy: ready for clinical practice?
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Liquid biopsy: ready for clinical practice?
Michail Ignatiadis MD, PhD
Jules Bordet Institut, Université Libre de Bruxelles
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Imaging and liquid biopsy: complementary tools
Anatomical & Functionalinformation
Genomic & Phenotypicinformation
Precicion Medicine
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Outline
Precision medicine
Cancer diagnosis
Early detection of
relapse
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Outline
Precision medicine
Cancer diagnosis
Early detection of
relapse
Identification of “driver” mutations
Identification ofgenomic alterations
responsible for secondary
resistance
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1st Liquid biopsy test approved
The cobas® EGFR Mutation Test v2 is a real-time PCR test for the qualitative
detection of defined EGFR mutations of in NSCLC patients
T790M
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ESR1 mutations worse OS (Bolero 2)
Chandarlapaty S et al, Jama Oncol 2016
ESR1 mutations 33% post 1st line vs11% starting 1st line
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Fribbens C et al, J Clin Oncol 2016
Fulvestrant better than exemestane in ESR1mut patients (Sofea)
PFS in ESR1 mutant PFS in ESR1 wild-type
Validation is needed!
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Fribbens C et al, J Clin Oncol 2016
Palbo benefit irrespective of baseline ESR1mut status (Paloma 3)
PFS in ESR1 mutant PFS in ESR1 wild-type
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Cristofanilli M et al, Lancet Oncol 2016
Palbo benefit irrespective of baseline PIK3CAmut status (Paloma 3)
PFS in PIK3CA mutant PFS in PIK3CA wild-type
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O’Leary B, et al, Nat Communications 2018
Early PIK3CA (clonal) but not ESR1 (subclonal) dynamics predict palbo benefit (Paloma 3)
Circulating DNA ratio D15/D1 (CDR15) in patients treated with fulvestrant and palbociclib
Median PIK3CA CDR15 Median ESR1 CDR15
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Acquired PIK3CA and ESR1 mutations (both arms) whereas acquired RB1 mutations (palbo arm)
O’Leary et al, Cancer Disco 2018
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Early versus late resistance and acquiredmutations at disease progression
O’Leary et al, Cancer Disco 2018
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Benefit from adding everolimus to exemestanedepend on ESR1 mut? (Bolero 2)
Chandarlapaty S et al, Jama Oncol 2016
Validation is needed!
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Primary/metastasis Plasma
DNA
pol
A
ACC
G
AA
A
C
CG
G
T
T
T
TT
H+H+
Ion AmpliSeqTM Cancer Hotspot Panel v2
(50 genes)
76% CONCORDANT 24% DISCORDANT
Tumor + / plasma +
(n=9)
Tumor + / plasma –
(n=2)
Tumor - / plasma +
(n=2)
Rothé F et al. Ann Oncol 2014
Plasma ctDNA: an alternative to metastatic biopsy
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Outline
Precision medicine
Cancer diagnosis
Early detection of
relapse
Identification of “driver” mutations
Identification ofgenomic alterations
responsible for secondary
resistance
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Treat CTC Trial
With residual disease after neoadjuvant CTX
Observation (n=87)*
HER2 “negative” BC
Positive
“High risk” after adjuvant CTX
CTC Blood test (National lab)
CTC Blood test (Central lab)
Negative: off study
Trastuzumab (n=87)*R
3 to 24 weeks3 to 24 weeks
Ignatiadis M, et al. Eur J Cancer. 2016
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Patients CTC-positive (after central image review): 95
Patients randomised: 63
• Consent withdrawal: 4• Primary tumor HER2-
positive: 6• Other 22
Patients with CTC test performed 1239
Patients registered: 1317
Trastuzumab: 31 Observation: 32
Trastuzumab: 29 Observation: 29
Study flow chart
Eligible for the primary endpoint
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Treatment arm
Total
(N=63)
Trastuzumab
(N=31)
Observation
arm
(N=32)
N (%) N (%) N (%)
Age in years
Median (range) 51.4 (31.9 - 69.4) 53.0 (31.4 - 68.6) 52.6 (31.4 - 69.4)
Pathological tumor size in
mm
Median (range) 25.0 (7.0 - 180.0) 24.0 (4.0 - 840.0) 24.0 (4.0 - 840.0)
Pathological lymph node
status
Negative 5 (16.1) 6 (18.8) 11 (17.5)
Positive 26 (83.9) 26 (81.3) 52 (82.5)
ER status
Negative 9 (29.0) 11 (34.4) 20 (31.7)
Positive 22 (71.0) 21 (65.6) 43 (68.3)
Chemotherapy
Neo-adjuvant 17 (54.8) 14 (43.8) 31 (49.2)
Adjuvant 14 (45.2) 18 (56.3) 32 (50.8)
Data are number of patients (%) or median (range). Ignatiadis M, et al. Ann Oncol 2018
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Fifty-eight patients were evaluable for the primary endpoint, 29 in each arm. In 9 of the 58 patients, CTC(s) were still detected at week 18: 5 in the trastuzumab and 4 in the observation arm (one-sided
Fisher exact test, p=0.765).
Efficacy results for primary objective
Ignatiadis M, et al. Ann Oncol 2018
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(months)
0 3 6 9 12 15 18 21 24 27
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk : Treatment arm
4 31 27 18 16 15 14 3 0 0
4 32 30 18 16 16 12 3 2 1
Trastuzumab
Observation arm
Invasive disease free survival
Patients(N)
Observed Events(O)
Median (95% CI)(Years)
% at 1 Year(s)(95% CI)
Trastuzumab 31 4 Not reached 84.8 (63.4, 94.2)
Observation 32 4 Not reached 93.8 (77.3, 98.4)
Invasive Disease Free Survival
Ignatiadis M, et al. Ann Oncol 2018
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B-47: Invasive Disease-Free Survival
No. at RiskChemoRxChemoRx+Trast
15581528
14231403
10031009
595591
140117
16031599
0
20
40
60
80
100
0 6 12 18 24 30 36 42 48 54 60
% D
ise
ase
-Fre
e
ChemoRxChemoRx+Trast
16031599
134 89.2%130 89.6%
HR 0.98 (95% CI 0.77-1.26) P=0.90
Treatment N Events 5 year EFS
This presentation is the intellectual property of the presenter. Contact them at [email protected] for permission to reprint and/or distribute
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Outline
Precision medicine
Cancer diagnosis
Early detection of
relapse
Identification of “driver” mutations
Identification ofgenomic alterations
responsible for secondary
resistance
![Page 23: Liquid biopsy: ready for clinical practice?](https://reader030.fdocuments.in/reader030/viewer/2022013005/61cc4b98fcf95962334d706d/html5/thumbnails/23.jpg)
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ctDNA for early diagnosis
HOPEDiagnose
cancer earlyon when still
curable
CHALLENGE:Sensitivity and specificity1 of
ctDNA for cancer
diagnosis
1 Mutations in cancer genes (e.g. p53 in 10% of non-cancer patients) occur even in individuals who will never develop cancer
(Lynnette Fernandez-Cuesta et al EBioMedicine 2016 )
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Challenges
• Physicians: Liquid biopsy in breast cancer is there for sometime but no clinical utility have been demonstrated’
• Pharma: ‘Why use the liquid biopsy approach to give my drugto a small proportion of patients, if I can give it to all comers?’
• Regulators: ‘You need a clear pathway for drug approval basedon ‘liquid biopsy’ test’
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Opportunities
• Administer the right drug only to those that need it and for as long as they needed (dream of personalized medicine)
• Develop a new model for drug development
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Acknowledgements
Women with breast cancer
Les Amis de l'Institut Bordet