Metastasis ósea de tumores sólidos · A Reduction in CTC Below 3 After the Initiation of Therapy Predicts Longer OS whereas an Increase in CTC Count to 3 or above Predicts a Shorter

Jesus Garcia-Foncillas MD PhD

Director

Liquid Biopsy

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Main issues about liquid biopsies

• New paradigm: Precision Medicine

• Heterogeneity & Dynamics

• Surrogate mirror for the tumor

• CTCs in colon cancer

• ctDNA:

– Technical approaches

– Heterogeneity & Dynamics

– Disease course

– Therapy monitoring






• ctDNA:



– Disease course


Precision Oncology:

Genomics-driven cancer medicine






• ctDNA:



– Disease course







• ctDNA:



– Disease course







• ctDNA:



– Disease course


• Enumeration

• Immunofluorescence

• Fluorescence in situ hybridization

• Next Generation Sequencing

• Mutation Detection

• Gene Expression

• Enumeration

• Immunofluorescence

Predictive Value: OS of MCRC Patients with <3 or >3 CTC

at Baseline (N=413)

%P

rob

ab

ilit

y o

f S

urv

iva

l

Time from Baseline Blood Draw (Months)

0 2 4 6 8 10 12 14 16 18 22 24 26 28 30

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

20

Logrank

p < 0.0001

18.5 Months

9.4

Months

Cox Hazard Ratio = 2.5

chi-square = 31.48

(p-value < 0.0001)

CTC / 7.5mL Median OS in

at Baseline N (%) Months (95% C.I.)

<3 CTC 305 (74%) 18.5 (15.5 to 21.2)

>3 CTC 108 (26%) 9.4 ( 7.5 to 11.6)

A Reduction in CTC Below 3 After the Initiation of Therapy Predicts

Longer OS whereas an Increase in CTC Count to 3 or above Predicts a

Shorter OS

*p-values not adjusted for multiple hypothesis tests

1

2

34

Curve Logrank

Comparison p-Value*

1 vs. 2 0.0007

1 vs. 3 <0.0001

1 vs. 4 <0.0001

2 vs. 3 0.0078

2 vs. 4 <0.0001

3 vs. 4 0.0001

%P

rob

ab

ilit

y o

f S

urv

iva

l

Time from Baseline Blood Draw (Months)

0 2 4 6 8 10 12 14 16 18 22 24 26 28 30

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

20

*p-values not adjusted for

multiple hypothesis tests

Median OS in

Group Description N (%) Months (95% C.I.)

1 <3 CTC at All Draws 303 (70%) 18.6 (15.9 to 22.5)

2 >3 CTC at BL & <3 CTC at Last Draw 74 (17%) 11.7 ( 9.4 to 18.7)

3 <3 CTC at Early Draw & >3 CTC at Last Draw 29 ( 7%) 7.1 ( 6.3 to 10.8)

4 >3 CTC at All Draws 24 ( 6%) 3.9 ( 2.5 to 5.4)






• ctDNA:



– Disease course







• ctDNA:



– Disease course


BEAMing

Pre-

AmplificationEmulsion PCR

Hybridization

Flow

Cytometry

Flow cytometry analysis

Mutant signal

Mutant

DNA

Mutant &

Wild-type DNA

Wild-type DNA

Wil

d-t

yp

e s

ign

al

Digital PCR






• ctDNA:



– Disease course







• ctDNA:



– Disease course


Cell-free tumor DNA in stage IV

(n = 177)

Cell-free tumor DNA in stage IV

Bettegowda et al, Sci Tran Med Feb 2014

Localized vs Metastatic Disease (n = 223)






• ctDNA:



– Disease course


ctDNA: Monitoring of tumor burden

Diehl et at. Nat Med. 2008

Cell-free tumor DNA

CEA

No detectable mutations in plasma

(n = 4)

Detectable mutations in plasma

(n = 14)

No detectable CEA (normal range boundary)

(n = 10)

Detectable CEA

(n = 8)

162 plasma samples from 18 pts (CRC pts)

p=0.0006

p=0.03

ctDNA: monitoring response

Baseline Imaging

8 weeks later

Courtesy of: Jeanne Tie, Peter Gibbs: Ann Oncol 2015

53 mCRC (ctDNA vs CEA and tumor burden)

Documents

Metastasis ósea de tumores sólidos · A Reduction in CTC Below 3 After the Initiation of Therapy Predicts Longer OS whereas an Increase in CTC Count to 3 or above Predicts a Shorter