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

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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
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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.

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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.

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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.

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Landmark Article

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

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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.

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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.

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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

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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.

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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.

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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)

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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)

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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.

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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.

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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.

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Other Tumor Markers

• The Evidence

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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

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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

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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

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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

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CA 27.29

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

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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.

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Study Objectives

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

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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

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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.

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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.

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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.

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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

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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.

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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

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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

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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.

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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

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Statistical Analysis

• PENDING!