Circulating Tumor Cells as a Tumor Marker for Metatastic Breast Cancer: A retrospective comparison w - PowerPoint PPT Presentation


Title: Circulating Tumor Cells as a Tumor Marker for Metatastic Breast Cancer: A retrospective comparison w


1
Circulating Tumor Cells as a Tumor Marker for
Metatastic Breast CancerA retrospective
comparison with alkaline phosphatase, lactate
dehydrogenase, CA 15-3, CA 27.29, and
carcinoembryonic antigen
  • Presented by
  • Jamie Koprivnikar, M.D.

Mentor Minetta Liu, M.D. Division of
Hematology/Oncology
2
Circulating Tumor Cells (CTCs)
  • Cancer cells that have detached from a solid
    tumor and entered the bloodstream
  • Found in patients with breast, prostate, ovarian,
    colorectal, and lung cancer.
  • They are very rare in patients who are healthy or
    who have benign disease.

3
Measuring CTCs
  • A sample of the patients peripheral blood is
    taken (a routine blood draw)
  • Cells expressing the epithelial-cell adhesion
    molecule are identified, labeled, and extracted
    using antibodies attached to magnetic beads.

4
Measuring CTCs
  • Next, different colored fluorescently labeled
    antibodies that bind specifically to either
    leukocytes (CD45) or epithelial cells
    (cytokeratin) are used to distinguish tumor cells
    from leukocytes.
  • A fluorescence-based microscopy system is used to
    count the number of tumor cells found in the
    peripheral blood.

5
Landmark Article
  • Circulating Tumor Cells, Disease Progression,
    and Survival in Metastatic Breast Cancer
  • Cristofanilli, et al.
  • N Engl J Med 2004 351 781-91.

6
Landmark Article
  • A prospective, multicenter study
  • 177 patients enrolled with metastatic breast
    cancer
  • Before starting a new treatment, patients had CTC
    levels and as well as radiographic staging
    studies obtained.

7
Landmark Article
  • CTCs were again collected 3-4 weeks after the
    initiation of the new therapy.
  • Both CTCs and imaging were repeated every 9 to 12
    weeks.
  • Imaging studies were interpreted according to the
    World Health Organization criteria without
    knowledge of CTC levels.

8
WHO Bidimensional CT Imaging
  • Partial Response (PR) 50 decrease in baseline
    sum tumor mass
  • Progressive Disease (PD) 25 increase in
    baseline sum tumor mass or the sum remains the
    same, but new lesion is noted
  • Stable Disease (S) increase with no new lesions

9
Landmark Article
  • A separate control group including 72
    premenopausal healthy women and 73 postmenopausal
    healthy women with no known illness and no
    history of cancer, 99 women with benign breast
    disease, and 101 women with other nonmalignant
    disease were also tested for CTCs.
  • None of the normal control subjects had 2 or more
    CTCs.

10
Landmark Article
  • In order to determine how many CTCs distinguished
    a significant prognostic difference, thresholds
    of 1 to 10,000 cells at baseline were correlated
    with progression-free survival.
  • A cutoff of 5 CTCs was found to distinguish poor
    versus favorable prognosis.

11
Landmark Article
  • Data from baseline CTC measurements
  • 5 CTCs
  • Median Progression 7 months 2.7 months
  • Free Survival (95 CI 5.8 to 8.9) (95 CI 2.1 to
    4.4)
  • Median Overall 18 months 10.1 months
  • Survival (95 CI 6.3 to 14.6)

12
Landmark Article
  • Data from follow-up CTC measurements
  • 5 CTCs
  • Median Progression 7 months 2.1 months
  • Free Survival (95 CI 5.8 to 8.4) (95 CI 1.8 to
    2.5)
  • Median Overall 18 months 8.2 months
  • Survival (95 CI 5.6 to 11.1)

13
Landmark Article
  • 33 patients with 5 CTCs at baseline were found
    to have
  • Median progression free and overall survival for
    these patients did not statistically differ from
    that of the group who had fewer than 5 CTCs both
    initially and at first follow-up.

14
Landmark Article
  • The behavior of those who had less than 5 CTCs at
    baseline, but 5 or more CTCs at follow-up did not
    statistically differ from those who had 5 or
    greater CTCs at both points in time.
  • Patients whose CTC level fell below 5 after their
    first therapy were found to have statistically
    longer progression free and overall survival than
    those who experienced a decline in CTCs, but
    whose level remained 5.

15
Landmark Article
  • In a multivariate analysis, the levels of CTCs at
    baseline and at the first follow-up visit were
    the strongest predictors of progression-free and
    overall survival.
  • CTCs gave an estimate of disease progression and
    survival earlier than estimations made wtih the
    use of traditional imaging methods.

16
Other Tumor Markers
  • The Evidence

17
Alkaline phophatase
  • Shown to decrease in those with metastatic breast
    cancer who had stable disease or partial response
    as compared to those with progressive disease
  • Generally normalizes in the face of disease
    stabilization/response
  • Does not always increase with disease progression

18
Lactate Dehydrogenase
  • Values that are greater than normal have been
    shown to be an independent prognosticator in
    patients with metastatic breast cancer
  • Shown to be useful, among other factors, as part
    of an equation to link response rate to patient
    characteristics

19
Carcinoembryonic Antigen (CEA)
  • Decreases of 20 or greater from the baseline
    value predicted response to therapy
  • Minimum level of 50 or greater was necessary to
    accurately predict response
  • Extremely high levels indicate a poor prognosis

20
CA 15-3
  • More sensitive than CEA with regards to both the
    presence of and progression of metastatic breast
    cancer
  • Not always reliable (may rise in the face of
    stable disease or partial response and vice
    versa)
  • More likely represents a surrogate marker for
    disease burden rather than an independent
    predictor of survival

21
CA 27.29
  • Similar to CA 15-3, but more sensitive and
    specific

22
Study Objectives
  • Primary Objective
  • To determine which tumor marker (LDH, Alk Phos,
    CEA, CA 15-3, CA 27.29, CTCs) best correlates
    with disease progression in metastatic breast
    cancer using standard radiographic imaging
    studies to determine disease course.

23
Study Objectives
  • Secondary Objective
  • To determine which tumor marker best correlates
    with overall survival in patients with metastatic
    breast cancer.

24
Study Population
  • Inclusion Criteria
  • Age 18 years old or older.
  • Histologically proven infiltrating carcinoma of
    the breast.
  • Stage IV breast cancer.
  • Radiographically measurable disease.
  • An understanding of the protocol and its
    requirements, risks, and discomforts.
  • The ability and willingness to sign an informed
    consent

25
Study Population
  • Exclusion Criteria
  • Pregnancy or lactation
  • Inability on the part of the patient to
    understand the informed consent or be compliant
    with the protocol.

26
Study Method
  • The study was carried out as a retrospective
    chart review of 65 patients who have thus far
    accrued on a prospective study, Circulating
    Tumor Cells Assessment of Treatment Efficacy in
    Metastatic Breast Cancer.

27
Study Method
  • As a part of this study, each patient had
  • Baseline determination of circulating tumor cells
    no more than 2 weeks before the initiation of a
    new systemic therapy
  • Baseline assessment of sites of disease with
    tumor measurements by CT scan, MRI or ultrasound
    done no more than 4 weeks before the initiation
    of a new systemic therapy.

28
Study Method
  • As a part of this study, each patient had
  • Repeat determination of CTCs every 3 to 4 weeks x
    6 then every 9 to 12 weeks
  • Radiographic tumor measurements every 9 to 12
    weeks or more frequently if clinically indicated

29
Study Method
  • Criteria for response were calculated using the
    RECIST criteria (Response Evaluation Criteria in
    Solid Tumors), which follows changes only in the
    largest diameter of measurable tumor.

30
Study Method
  • Criteria for Response
  • Clinical complete response the complete
    disappearance of all target lesions
  • Pathologic complete response no histologic
    evidence of residual disease
  • Partial response at least a 30 decrease in the
    sum of the longest diameter of the target lesions
    in comparison to baseline measurements

31
Study Method
  • Criteria for Response
  • Stable Disease neither sufficient shrinkage to
    qualify for a partial response nor sufficient
    growth to qualify for progressive disease
  • Progression of Disease at least a 20 increase
    in the sum of the longest diameter of the target
    lesions in comparison to baseline measurements OR
    the appearance of new lesions

32
Study Method
  • A retrospective chart review was performed on all
    patients enrolled in this study as of July 31,
    2007.
  • This review collected values for Alkaline
    Phospatase, LDH, CEA, CA 15-3, and CA 27.29
    obtained throughout the same range of dates over
    which CTCs were collected.

33
Results
  • Data obtained for 58 patients
  • Alkaline phosphatase data available for 57/58
    patients
  • LDH data available for 25/58 patients
  • CEA data available for 6/58 patients
  • CA 15-3 data available for 5/58 patients
  • CA 27.29 data available for 18/58 patients

34
Statistical Analysis
  • PENDING!
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Circulating Tumor Cells as a Tumor Marker for Metatastic Breast Cancer: A retrospective comparison w

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Title: Circulating Tumor Cells as a Tumor Marker for Metatastic Breast Cancer: A retrospective comparison w


1
Circulating Tumor Cells as a Tumor Marker for
Metatastic Breast CancerA retrospective
comparison with alkaline phosphatase, lactate
dehydrogenase, CA 15-3, CA 27.29, and
carcinoembryonic antigen
  • Presented by
  • Jamie Koprivnikar, M.D.

Mentor Minetta Liu, M.D. Division of
Hematology/Oncology
2
Circulating Tumor Cells (CTCs)
  • Cancer cells that have detached from a solid
    tumor and entered the bloodstream
  • Found in patients with breast, prostate, ovarian,
    colorectal, and lung cancer.
  • They are very rare in patients who are healthy or
    who have benign disease.

3
Measuring CTCs
  • A sample of the patients peripheral blood is
    taken (a routine blood draw)
  • Cells expressing the epithelial-cell adhesion
    molecule are identified, labeled, and extracted
    using antibodies attached to magnetic beads.

4
Measuring CTCs
  • Next, different colored fluorescently labeled
    antibodies that bind specifically to either
    leukocytes (CD45) or epithelial cells
    (cytokeratin) are used to distinguish tumor cells
    from leukocytes.
  • A fluorescence-based microscopy system is used to
    count the number of tumor cells found in the
    peripheral blood.

5
Landmark Article
  • Circulating Tumor Cells, Disease Progression,
    and Survival in Metastatic Breast Cancer
  • Cristofanilli, et al.
  • N Engl J Med 2004 351 781-91.

6
Landmark Article
  • A prospective, multicenter study
  • 177 patients enrolled with metastatic breast
    cancer
  • Before starting a new treatment, patients had CTC
    levels and as well as radiographic staging
    studies obtained.

7
Landmark Article
  • CTCs were again collected 3-4 weeks after the
    initiation of the new therapy.
  • Both CTCs and imaging were repeated every 9 to 12
    weeks.
  • Imaging studies were interpreted according to the
    World Health Organization criteria without
    knowledge of CTC levels.

8
WHO Bidimensional CT Imaging
  • Partial Response (PR) 50 decrease in baseline
    sum tumor mass
  • Progressive Disease (PD) 25 increase in
    baseline sum tumor mass or the sum remains the
    same, but new lesion is noted
  • Stable Disease (S) increase with no new lesions

9
Landmark Article
  • A separate control group including 72
    premenopausal healthy women and 73 postmenopausal
    healthy women with no known illness and no
    history of cancer, 99 women with benign breast
    disease, and 101 women with other nonmalignant
    disease were also tested for CTCs.
  • None of the normal control subjects had 2 or more
    CTCs.

10
Landmark Article
  • In order to determine how many CTCs distinguished
    a significant prognostic difference, thresholds
    of 1 to 10,000 cells at baseline were correlated
    with progression-free survival.
  • A cutoff of 5 CTCs was found to distinguish poor
    versus favorable prognosis.

11
Landmark Article
  • Data from baseline CTC measurements
  • 5 CTCs
  • Median Progression 7 months 2.7 months
  • Free Survival (95 CI 5.8 to 8.9) (95 CI 2.1 to
    4.4)
  • Median Overall 18 months 10.1 months
  • Survival (95 CI 6.3 to 14.6)

12
Landmark Article
  • Data from follow-up CTC measurements
  • 5 CTCs
  • Median Progression 7 months 2.1 months
  • Free Survival (95 CI 5.8 to 8.4) (95 CI 1.8 to
    2.5)
  • Median Overall 18 months 8.2 months
  • Survival (95 CI 5.6 to 11.1)

13
Landmark Article
  • 33 patients with 5 CTCs at baseline were found
    to have
  • Median progression free and overall survival for
    these patients did not statistically differ from
    that of the group who had fewer than 5 CTCs both
    initially and at first follow-up.

14
Landmark Article
  • The behavior of those who had less than 5 CTCs at
    baseline, but 5 or more CTCs at follow-up did not
    statistically differ from those who had 5 or
    greater CTCs at both points in time.
  • Patients whose CTC level fell below 5 after their
    first therapy were found to have statistically
    longer progression free and overall survival than
    those who experienced a decline in CTCs, but
    whose level remained 5.

15
Landmark Article
  • In a multivariate analysis, the levels of CTCs at
    baseline and at the first follow-up visit were
    the strongest predictors of progression-free and
    overall survival.
  • CTCs gave an estimate of disease progression and
    survival earlier than estimations made wtih the
    use of traditional imaging methods.

16
Other Tumor Markers
  • The Evidence

17
Alkaline phophatase
  • Shown to decrease in those with metastatic breast
    cancer who had stable disease or partial response
    as compared to those with progressive disease
  • Generally normalizes in the face of disease
    stabilization/response
  • Does not always increase with disease progression

18
Lactate Dehydrogenase
  • Values that are greater than normal have been
    shown to be an independent prognosticator in
    patients with metastatic breast cancer
  • Shown to be useful, among other factors, as part
    of an equation to link response rate to patient
    characteristics

19
Carcinoembryonic Antigen (CEA)
  • Decreases of 20 or greater from the baseline
    value predicted response to therapy
  • Minimum level of 50 or greater was necessary to
    accurately predict response
  • Extremely high levels indicate a poor prognosis

20
CA 15-3
  • More sensitive than CEA with regards to both the
    presence of and progression of metastatic breast
    cancer
  • Not always reliable (may rise in the face of
    stable disease or partial response and vice
    versa)
  • More likely represents a surrogate marker for
    disease burden rather than an independent
    predictor of survival

21
CA 27.29
  • Similar to CA 15-3, but more sensitive and
    specific

22
Study Objectives
  • Primary Objective
  • To determine which tumor marker (LDH, Alk Phos,
    CEA, CA 15-3, CA 27.29, CTCs) best correlates
    with disease progression in metastatic breast
    cancer using standard radiographic imaging
    studies to determine disease course.

23
Study Objectives
  • Secondary Objective
  • To determine which tumor marker best correlates
    with overall survival in patients with metastatic
    breast cancer.

24
Study Population
  • Inclusion Criteria
  • Age 18 years old or older.
  • Histologically proven infiltrating carcinoma of
    the breast.
  • Stage IV breast cancer.
  • Radiographically measurable disease.
  • An understanding of the protocol and its
    requirements, risks, and discomforts.
  • The ability and willingness to sign an informed
    consent

25
Study Population
  • Exclusion Criteria
  • Pregnancy or lactation
  • Inability on the part of the patient to
    understand the informed consent or be compliant
    with the protocol.

26
Study Method
  • The study was carried out as a retrospective
    chart review of 65 patients who have thus far
    accrued on a prospective study, Circulating
    Tumor Cells Assessment of Treatment Efficacy in
    Metastatic Breast Cancer.

27
Study Method
  • As a part of this study, each patient had
  • Baseline determination of circulating tumor cells
    no more than 2 weeks before the initiation of a
    new systemic therapy
  • Baseline assessment of sites of disease with
    tumor measurements by CT scan, MRI or ultrasound
    done no more than 4 weeks before the initiation
    of a new systemic therapy.

28
Study Method
  • As a part of this study, each patient had
  • Repeat determination of CTCs every 3 to 4 weeks x
    6 then every 9 to 12 weeks
  • Radiographic tumor measurements every 9 to 12
    weeks or more frequently if clinically indicated

29
Study Method
  • Criteria for response were calculated using the
    RECIST criteria (Response Evaluation Criteria in
    Solid Tumors), which follows changes only in the
    largest diameter of measurable tumor.

30
Study Method
  • Criteria for Response
  • Clinical complete response the complete
    disappearance of all target lesions
  • Pathologic complete response no histologic
    evidence of residual disease
  • Partial response at least a 30 decrease in the
    sum of the longest diameter of the target lesions
    in comparison to baseline measurements

31
Study Method
  • Criteria for Response
  • Stable Disease neither sufficient shrinkage to
    qualify for a partial response nor sufficient
    growth to qualify for progressive disease
  • Progression of Disease at least a 20 increase
    in the sum of the longest diameter of the target
    lesions in comparison to baseline measurements OR
    the appearance of new lesions

32
Study Method
  • A retrospective chart review was performed on all
    patients enrolled in this study as of July 31,
    2007.
  • This review collected values for Alkaline
    Phospatase, LDH, CEA, CA 15-3, and CA 27.29
    obtained throughout the same range of dates over
    which CTCs were collected.

33
Results
  • Data obtained for 58 patients
  • Alkaline phosphatase data available for 57/58
    patients
  • LDH data available for 25/58 patients
  • CEA data available for 6/58 patients
  • CA 15-3 data available for 5/58 patients
  • CA 27.29 data available for 18/58 patients

34
Statistical Analysis
  • PENDING!
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