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

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

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Most Important Questions After a Diagnosis of
Breast Cancer

• How bad or aggressive is the tumor
• Will the tumor recur
• Is adjuvant chemotherapy necessary?

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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

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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

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uPA in Metastasis

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

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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

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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

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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

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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

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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

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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

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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)
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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
• 
  

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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

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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

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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

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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

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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

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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

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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

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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 ?

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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

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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

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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.