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Circulating tumor cells: are they predictive markers?. AGA/ASCO/ASTRO/SSO Gastrointestinal Cancers Symposium Orlando, FL January 26, 2008. Neal J. Meropol, M.D. Fox Chase Cancer Center. “Predictive” vs. “Prognostic”. Predictive : explains variability in response to treatment

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Aga asco astro sso gastrointestinal cancers symposium orlando fl january 26 2008

Circulating tumor cells: are they predictive markers?

AGA/ASCO/ASTRO/SSO

Gastrointestinal Cancers Symposium

Orlando, FL

January 26, 2008

Neal J. Meropol, M.D.

Fox Chase Cancer Center


Predictive vs prognostic
“Predictive” vs. “Prognostic”

  • Predictive: explains variability in response to treatment

    • Traditional application before treatment

  • Prognostic: explains variability irrespective of treatment


Natural history of circulating tumor cells
Natural History of Circulating Tumor Cells

Paterlini-Brechot and Benali, Cancer Letters, 2007


Potential advantages of circulating tumor cells ctcs compared to other blood markers
Potential advantages of circulating tumor cells (CTCs) compared to other blood markers

  • Representative of tumor access to circulation

  • Permits multiple simultaneous analyses

    • Enumerate, phenotype, gene expression

  • Cytopathology

  • in vivo pharmacodynamic assessment, gene expression profiling

  • Sensitivity/Specificity


Why study ctcs
Why Study CTCs? compared to other blood markers

  • Prognosis

  • Monitor disease course

    • Minimal residual disease

    • Early relapse

    • Response to therapy

  • Treatment selection

  • Drug development (pharmacodynamics)

    • Target acquisition

    • Down stream effects


Methods for ctc detection
Methods for CTC Detection compared to other blood markers

  • Density gradient

  • Immunomagnetic separation (beads, ferrofluid)

  • Size-based filtration

    Count

    Cytopathology

    RT-PCR

    Genotyping

20%-70% of patients with colorectal cancer have detectable CTCs


Immunomagnetic separation

Stations compared to other blood markers

2 & 3

7.5 ml

Plasma

Magnetic

Primary

Addition of

Blood +

Aspiration &

Incubations

Magnetic

Cytokeratin-PE

6.5mL

Addition of

Separation &

CD45-APC, &

Buffer

EPCAM Ferrofluid

Resuspension

DAPI

Immunomagnetic Separation

Station 1

Station 4

Station 5

Centrifuge

Place on

Instrument

-

-

Described in: WJ Allard et al, Clin Cancer Res 10: 6897-6904, 2004


Immunomagnetic separation1

Staining Incubation, compared to other blood markers

Final

Magnetic Wash &

Resuspension

Free Particle

Removal

Immunomagnetic Separation

Image Gallery

Stations 6,7, & 8

Station 9a

Station 9b

Automatic Transfer of Sample for Fluorescent Image Analysis


Characterization of ctcs by flow cytometry
Characterization of CTCs by Flow Cytometry compared to other blood markers

SJ Cohen et al. Clin Colorectal Cancer, 2006

CTC, green and red

EGFR+, red

WBC, blue

Beads, yellow


Circulating tumor cells (CTC) predict progression free (PFS) and overall survival (OS) in patients with metastatic colorectal cancer

ASCO 2007

N. J. Meropol, S. J. Cohen, N. Iannotti, B. H. Saidman, K. D. Sabbath, M. C. Miller, G. V. Doyle, H. Tissing, L. W.M.M. Terstappen, C.J.A. Punt

Fox Chase Cancer Center, Philadelphia, PA; Hematology Oncology Associates, Port St. Lucie, FL; Medical Oncology Associates, Kingston, PA; Medical Oncology and Hematology, PC, Waterbury, CT; Immunicon Corporation, Huntingdon Valley, PA; Radboud University Medical Center, Nijmegen, The Netherlands


Objectives and eligibility
Objectives and Eligibility and overall survival (OS) in patients with metastatic colorectal cancer

Overall Objective

To determine the association between circulating tumor cell number and clinical outcomes in patients with metastatic colorectal cancer

Eligibility

Adults with measurable metastatic colorectal cancer, initiating first-, second-, or third-line therapy


Methods
Methods and overall survival (OS) in patients with metastatic colorectal cancer

  • Multicenter international study

  • Radiographic tumor measurement at baseline and every 6-12 weeks after treatment initiation (RECIST criteria)

  • Peripheral blood was collected for CTC enumeration at baseline and subsequently at 1-2, 3-5, 6-12, and 13-20 weeks after treatment initiation

  • Blood mailed overnight at room temperature, and processed at 1 of 4 laboratories within 96 hours


26 and overall survival (OS) in patients with metastatic colorectal cancer

24

22

20

18

16

Median OS from Baseline (Months)

14

12

10

8

6

4

2

53%

47%

33%

26%

21%

18%

16%

14%

13%

12%

11%

0

0

>= 1

>= 2

>= 3

>= 4

>= 5

>= 6

>= 7

>= 8

>= 9

>= 10

CTC / 7.5mL of Blood (Baseline Draw)

Median OS for Patients with Metastatic Colorectal Cancer Based Upon number of CTC Prior to the Initiation of Therapy

(N=413)

ASCO 2007


Baseline ctc progression free survival
Baseline CTC: Progression Free Survival and overall survival (OS) in patients with metastatic colorectal cancer

100%

CTC/7.5 mL Median in Months

(95% CI)

<3 CTCs 7.9 (7.0 - 8.6)

≥3 CTCs 4.5 (3.7 - 6.3)

90%

80%

70%

60%

50%

P = 0.0002

% Progression Free

40%

30%

20%

10%

0%

0

8

14

16

18

20

22

24

26

28

2

6

10

12

30

4

Time from Baseline Blood Draw (Months)

<3 CTCs

305

269

229

187

138

88

44

32

20

15

8

6

3

0

0

0

≥3 CTCs

108

84

60

42

28

16

8

3

2

2

1

0

0

0

0

0

ASCO 2007


Baseline ctc overall survival
Baseline CTC: Overall Survival and overall survival (OS) in patients with metastatic colorectal cancer

CTC/7.5 mL Median in Months (95% CI)

<3 CTC 18.5 (15.5 - 21.2)

≥3 CTC 9.4 (7.5 - 11.6)

100%

90%

80%

70%

P < 0.0001

60%

50%

% Survival

40%

30%

20%

10%

0%

0

8

14

16

18

20

22

24

26

28

2

6

10

12

30

4

Time from Baseline Blood Draw (Months)

<3 CTC

305

289

276

252

227

180

134

107

78

60

43

32

22

11

4

2

≥3 CTC

108

102

86

66

49

36

24

13

12

11

7

4

2

1

1

0

ASCO 2007


Ctc during treatment pfs
CTC During Treatment: PFS and overall survival (OS) in patients with metastatic colorectal cancer

100%

N Median PFS in Months (95% CI)

<3 CTC ≥3 CTC

1-2 wks 315 7.3 (6.5 - 8.1) 3.8 (1.9 - 5.1)

3-5 wks 329 6.8 (6.1 - 7.6) 1.9 (1.2 - 4.4)

6-12 wks 284 6.5 (5.8 - 7.7) 2.0 (0.5 - 2.5)

90%

80%

70%

60%

50%

P < 0.0001 at each timepoint

%Probability of Progression Free Survival

40%

30%

20%

10%

0%

0

8

14

16

18

20

22

24

26

28

2

6

10

12

30

4

Time from Blood Draw (Months)

ASCO 2007


Ctc during treatment overall survival
CTC During Treatment: Overall Survival and overall survival (OS) in patients with metastatic colorectal cancer

Median OS in Months (95% CI)

N <3 CTC ≥3 CTC

1-2 wks 357 15.7 (14.3 - 18.4) 6.1 (4.9 - 8.9)

3-5 wks 333 16.4 (14.1 - 18.3) 4.4 (2.6 - 8.7)

6-12 wks 310 15.8 (13.8 - 19.2)3.3 (1.8 - 5.6)

100%

90%

80%

70%

P < 0.0001 at each timepoint

60%

%Probability of Survival

50%

40%

30%

20%

10%

0%

0

8

14

16

18

20

22

24

26

28

2

6

10

12

30

4

Time from Blood Draw (Months)

ASCO 2007


Predictors of pfs and os multivariable model baseline n 373
Predictors of PFS and OS: and overall survival (OS) in patients with metastatic colorectal cancerMultivariable Model – Baseline (N=373)

ASCO 2007


Predictors of pfs and os multivariable model 3 5 weeks n 302
Predictors of PFS and OS: and overall survival (OS) in patients with metastatic colorectal cancerMultivariable Model – 3-5 Weeks (N=302)

ASCO 2007


Circulating tumor cells at time of 1 st followup image add prognostic information
Circulating Tumor Cells at Time of 1 and overall survival (OS) in patients with metastatic colorectal cancerst Followup Image Add Prognostic Information

CTC Response N OS in Months

(95% CI)

<3 CTC S/PR/CR 271 18.8 (17.0 - 25.1)

<3 CTC PD/Death 64 8.3 (5.8 - 11.2)

>3 CTC S/PR/CR 13 7.1 (5.4 - 10.8)

>3 CTC PD/Death 16 3.1 (2.0 - 4.4)

100%

90%

80%

70%

vs. P < 0.0001

60%

50%

%Probability of Survival

40%

30%

20%

10%

0%

0

8

14

16

18

20

22

24

26

28

2

6

10

12

30

4

Time from Baseline Blood Draw (Months)

ASCO 2007


Circulating tumor cells at time of 1 st followup image add prognostic information1
Circulating Tumor Cells at Time of 1 and overall survival (OS) in patients with metastatic colorectal cancerst Followup Image Add Prognostic Information

CTC Response N OS in Months

(95% CI)

<3 CTC S/PR/CR 271 18.8 (17.0 - 25.1)

<3 CTC PD/Death 64 8.3 (5.8 - 11.2)

>3 CTC S/PR/CR 13 7.1 (5.4 - 10.8)

>3 CTC PD/Death 16 3.1 (2.0 - 4.4)

100%

90%

80%

70%

60%

50%

%Probability of Survival

vs. P = 0.0001

40%

30%

20%

10%

0%

0

8

14

16

18

20

22

24

26

28

2

6

10

12

30

4

Time from Baseline Blood Draw (Months)

ASCO 2007


Circulating tumor cells at time of 1 st followup image add prognostic information2
Circulating Tumor Cells at Time of 1 and overall survival (OS) in patients with metastatic colorectal cancerst Followup Image Add Prognostic Information

CTC Response N OS in Months

(95% CI)

<3 CTC S/PR/CR 271 18.8 (17.0 - 25.1)

<3 CTC PD/Death 64 8.3 (5.8 - 11.2)

>3 CTC S/PR/CR 13 7.1 (5.4 - 10.8)

>3 CTC PD/Death 16 3.1 (2.0 - 4.4)

100%

90%

80%

70%

60%

50%

%Probability of Survival

40%

30%

20%

10%

0%

0

8

14

16

18

20

22

24

26

28

2

6

10

12

30

4

Time from Baseline Blood Draw (Months)

ASCO 2007


Decrease in ctc at 3 5 weeks is associated with improved pfs in patients with 3 ctc at baseline
Decrease in CTC at 3-5 Weeks is Associated with Improved PFS in Patients with > 3 CTC at Baseline

100%

Baseline 3-5 wks N Med PFS

(95% CI)

≥3 CTC <3 CTC 52 6.2 (4.6 - 7.0)

≥3 CTC ≥3 CTC 28 1.6 (1.2 - 2.7)

P = 0.02

90%

80%

70%

60%

50%

% Probability of Progression Free Survival

40%

30%

20%

10%

0%

0

8

14

16

18

20

22

24

26

28

2

4

6

10

12

30

Time from 3-5 Week Blood Draw (Months)

ASCO 2007


Ctc association with pfs and os by lines of therapy
CTC Association with PFS and OS by Lines of Therapy in Patients with

1st line

HR=2.22 (1.49-3.30)

HR=1.44 (1.04-1.98)

PFS

OS

HR=1.90 (1.26-2.85)

2nd line

HR=2.98 (1.85-4.77)

Cohen et al. AGA/ASCO/ASTRO/SSO GI Cancers Symposium, 2008


Conclusions
Conclusions in Patients with

  • In patients with metastatic colorectal cancer, CTC number before and after initiation of treatment is a significant independent predictor of progression free survival and overall survival

  • CTC enumeration is complementary to imaging, and may provide early evidence of treatment success or failure

  • Further research is required to determine whether change in therapy based upon elevated CTC number at early followup will improve patient outcomes


Are ctcs predictive markers
Are CTCs Predictive Markers? in Patients with

Maybe

  • Traditional application before treatment

    • no data yet regarding role of phenotyping/genotyping CTCs and response to therapy

  • Alternative application early after treatment initiation

    • suggestive evidence that CTCs indicate resistance to treatment


Clinical validation study design requirements
Clinical validation study design requirements in Patients with

  • Standardized assay platform for clinical decision making

  • Prospective randomized trial

    • archival well-annotated clinical specimens do not exist

  • Randomized population of adequate size to answer clinical question

    • Requires previous validation with assay platform


Metastatic disease study design early change in therapy

Continue Treatment A in Patients with

Favorable CTCs?

Yes*

Continue Treatment A

No

R

Change to Treatment B

Metastatic disease study design:early change in therapy

Assess at 1-3 weeks

Begin Treatment A

*assumes that continuation of Treatment A is best in Favorable CTC group


Metastatic disease study design selection of initial therapy

Standard initial therapy in Patients with

Yes*

Standard initial therapy

No

R

More aggressive initial therapy

Metastatic disease study design:selection of initial therapy

Favorable CTCs?

*assumes that standard therapy is “best” in Favorable CTC group


Surveillance study design 1 randomize early

Routine surveillance in Patients with

R

Routine surveillance + CTC evaluation, with aggressive intervention if CTC “recurrence”

Surveillance study design 1: randomize early

Resected patients at risk for recurrence


Surveillance study design 2 randomize later

Continue routine surveillance in Patients with

R

CTC “Recurrence”

Aggressive intervention

Surveillance study design 2: randomize later

Resected patients at risk for recurrence

Routine surveillance plus CTC evaluation


Many questions remain
Many Questions Remain in Patients with

  • What are “circulating tumor cells”?

  • Are CTCs the same as in situ cancer?

  • How does cell separation process affect gene expression?

  • How can CTCs be used in the drug development process?

  • How can CTCs be integrated into routine patient care?


The end
The End in Patients with


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