uPA in Breast Cancer: From Pilot Studies to Recommendation for Clinical Use - PowerPoint PPT Presentation

Loading...

PPT – uPA in Breast Cancer: From Pilot Studies to Recommendation for Clinical Use PowerPoint presentation | free to view - id: ee609-ZDc1Z



Loading


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation
Title:

uPA in Breast Cancer: From Pilot Studies to Recommendation for Clinical Use

Description:

... adjuvant ... that patients selected for adjuvant chemotherapy based on uPA ... ADJUVANT CHEMOTHERAPY FOR BREAST CANCER: OVERVIEW OF RANDOMISED ... – PowerPoint PPT presentation

Number of Views:63
Avg rating:3.0/5.0
Slides: 26
Provided by: duf54
Category:

less

Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: uPA in Breast Cancer: From Pilot Studies to Recommendation for Clinical Use


1
  • uPA in Breast Cancer From Pilot Studies to
    Recommendation for Clinical Use
  • Professor Joe Duffy
  • St Vincents University Hospital and University
    College, Dublin

2
Most Important Questions After a Diagnosis of
Breast Cancer
  • How bad or aggressive is the tumor
  • Will the tumor recur
  • Is adjuvant chemotherapy necessary?

3
Most Important Questions After a Diagnosis of
Breast Cancer
  • How bad or aggressive is the tumor
  • Will the tumor recur
  • Is adjuvant chemotherapy necessary?
  • Answer to these 3 questions depends on the likely
    formation of distant metastasis

4
METASTASIS
  • Main cause of death in patients with cancer
  • Most distant metastases are essentially incurable
  • Metastasis is not a universal feature of
    malignancy
  • Tumors vary widely in their ability to metastasise

5
uPA in Metastasis
  • Classical studies in animal models showed that
    uPA was causally involved in cancer invasion and
    metastasis

6
Hypothesis
  • Data from model systems show that uPA is involved
    in metastasis
  • Levels of uPA in human tumors may therefore
    predicts metastatic potential, ie, uPA may be a
    prognostic marker in cancer
  • Duffy MJ Eur J Cancer 198723583

7
Seminal Study on uPA in Breast Cancer DFI as End
Point
  • Urokinase-plasminogen activator, a marker for
    aggressive breast carcinomas,
  • Preliminary report.
  • Duffy et al. Cancer. 198862531-3

8
Confirmation of Finding in Pilot Study
  • Confirmed that uPA also predicted shortened
    overall survival,
  • Duffy et al, Lancet 199013335868
  • Confirmed findings with a different assay for uPA
    and a different patient cohort.
  • Showed that uPA predicted outcome independent of
    traditional factors
  • Duffy et al, Cancer Res 1990506827-9

9
Further Conirmation of Prognostic Impact of uPA
in Breast Cancer
  • Showed that uPA predicted outcome in different
    subgroups of patients with breast cancer
    including node-negative patients.
  • Duffy et al. Cancer 1994742276-80.
  • Confirmed above results with a kit assay for uPA
  • Duffy et al, Clin Chem 1998441177-83

10
uPA as a Prognostic Factor in Breast Cancer
Independent Confirmation
  • Duffy et al DUBLIN
    1988
  • Janicke et al MUNICH
    1989
  • Cooke et al LONDON
    1991
  • Spyratos et al PARIS
    1992
  • Foekens et al ROTTERDAM 1992
  • Grondahl-Hansen et al COPENHAGEN 1993
  • Kute et al N CAROLINA
    1994
  • Knoop et al ODENSE
    1995

11
Clinical utility of tumor markersLevels of
evidence
  • I high powered prospective study or meta/pooled
    analysis
  • II prospective drug trial, marker secondary aim
  • III large retrospective studies
  • IV small retrospective study with clinical data
  • V small pilot studies.
  • Hayes
    D, JNCI, 1996

12
CHEMO-N0 Study Design
uPA and PAI-1 low
(A)
no therapy

(55 of all pts.)
Inclusion criteria node-negative, M0 gt 1cm, lt5
cm pre- or postmenop. receptor-pos. or -neg.
Stratification
(B 1)
CMF X 6
(45 of pts.)
Randomisation
uPA and/or PAI-1 high

(B 2)
no therapy
informedconsent refused
no therapy or CMF 6
(B 3)
13
uPA/PAI-1 Multicenter Prospective Randomized
Trial Main Conclusions
  • Trial confirmed the prognostic impact of uPA and
    PAI-1 in lymph node-negative breast cancer
    patients
  • Trial showed that patients selected for adjuvant
    chemotherapy based on uPA/PAI-1 had a better
    outcome than those that did not receive
    chemotherapy
  • Janicke et al JNCI
    200293913


14
Pooled Analysis of uPA/PAI-1 EORTC Study
  • 18 data sets, 8377 patients
  • Published, 11 unpublished 7
  • Median follow-up 79 months
  • Look et al. JNCI 200294116

15
(No Transcript)
16
Pooled Analysis of uPA/PAI-1 EORTC Study
  • Both uPA and PAI-1 were independent prognostic
    factors
  • uPA/PAI-1 ranked second to nodes but stronger
    than size, grade, HR, age
  • uPA/PAI-1 prognostic in N- and N patients
  • uPA/PAI-1 prognostic in untreated N- patients
  • uPA/PAI-1 together better than either alone
  • Look et al. JNCI
    200294116

17
Axillary Node (AN)-Negative Breast Cancer
  • With screening, 2/3 of newly diagnosed breast ca
    patients are node negative
  • 70 are cured by surgery and RT
  • 30 develop metastasis by 10 yr
  • Currently, there is no reliable test to
    differentiate between indolent and aggressive
    tumors

18
Node-Negative Breast Cancer Treatment Dilemma
  • Circumventing the DilemmaTreat all or almost all
    node-negative patients with adjuvant chemotherapy
  • Problem Only a minority of patients will benefit
    but most will suffer toxic side-effects

19
CHEMOTHERAPY FOR BREAST CANCER OVERVIEW OF
RANDOMISED TRIALS
  • 18,000 women
  • 47 trials of chemotherapy vs no chemo
  • Change in 10-yr survival (node-negative
    patients)
  • lt50 yr 71?78
  • 50-69 yr 67?69
  • Lancet
    1998352930

20
ADJUVANT CHEMOTHERAPY FOR BREAST CANCER OVERVIEW
OF RANDOMISED TRIALS
  • 145,000 women
  • 194 trials of chemotherapy vs no chemo
  • Absolute Improvement in Mortality ()
  • 5 yr 10
    yr 15 yr
  • Women lt50 yr 4.7 7.9
    10
  • Women 50-69 yr 2.6 2.9
    3.0
  • Lancet 20053651687

21
SIDE EFFECTS OF CHEMOTHERAPY (CMF)
  • Side effect
    affected
  • Nausea 43
  • Vomiting 42
  • Alopecia 40
  • Ovarian failure 70
  • Weight gain 12
  • Diarrhea 4.5
  • N Eng J
    Med 20013441997

22
Question
  • Should most node-negative breast cancer patients
    be treated with chemotherapy so that a small
    minority benefit while a large proportion suffer
    from adverse toxic effects ?

23
Rational Way Forward
  • Develop and validate markers that will reliably
    differentiate between patients with aggressive
    and indolent disease.
  • Metastasis is the main causes of mortality in
    cancer. Since uPA is causally involved in
    metastasis, it should be a strong marker of
    metastatic potential and thus of prognosis

24
uPA and PAI-1 Clinical Use
  • For selecting node-negative breast cancer
    patients who do not need adjuvant chemotherapy,
    ie, patients with low levels of uPA/PAI-1 may be
    able to avoid the side effects and costs of
    adjuvant chemotherapy

25
uPA and PAI-1 ASCO Recommendation for Clinical
Use (2007)
  • uPA/PAI-1 may be used for the determination of
    prognosis in patients with newly diagnosed, node
    negative breast cancer. Low levels of both
    markers are associated with a sufficiently low
    risk of recurrence, especially in hormone
    receptorpositive women who will receive adjuvant
    endocrine therapy, that chemotherapy will only
    contribute minimal additional benefit.
About PowerShow.com