C-erbB-4 in Non-Small Cell Lung Cancer: Correlation with Response to Gemcitabine Cisplatin Chemotherapy

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C-erbB-4 in Non-Small Cell Lung Cancer
Correlation with Response to Gemcitabine
Cisplatin Chemotherapy
O. Merimsky, A. Staroselsky, N. Wigler, Y.
Schwartz, A. Mann, S. Marmor, M. Inbar, J.
Greif Departments of Oncology, Pathology and
Pulmonology Tel-Aviv Sourasky Medical Center
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C-erbB-4 in Non-Small Cell Lung Cancer
Correlation with Response to Gemcitabine
Cisplatin Chemotherapy
Ann Oncol 2001
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Background Patient Selection in Daily Practice

• Traditional Criteria Patient Characteristics
• sex, age, KPS, blood tests
• histology, stage
• co-morbidity (medical problem)
• vital organ reserve / involvement
• C/I to drugs
• Modern Criteria Expression of Molecular Markers
• Choice of therapeutic agents
• Overexpression of c-erbB-2 in breast cancer
  resistance to hormone and / or non-ADR based
  chemotherapy
• Assays for drug resistance
• Targeting by MoAb w/o chemotherapy
• HER2/neu receptor in breast cancer (Trastuzumab)
• CD-20 antigen in NHL (Rituximab)

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Molecular Markers in NSCLC Prognostication

• p53, Rb, CD-44, and factor viiidecreased
  cancer-specific survival in women Veale 1987
• erbB-2 decreased cancer-specific survival in
  men Veale 1987
• erbB-2 expression, p53 expression, higher Ki-67
  index poor prognosis, early recurrence and
  cancer-death include Strauss 1995
• p53, factor viii, erbB-2 and CD44 risk of
  recurrence and death in stage I disease D'Amico
  1999
• epidermal growth factor receptor (EGFR) and p53
  proteinsshorter survival and higher metastatic
  potential Ohsaki 2000

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C-erbB Family

• Overexpression of the c-erbB-1 and c-erbB-2
  receptors is a factor of poor prognosis in a
  variety of malignancies Yu et al. Cancer Res
  1994
• Expression of c-erbB-3 and c-erbB-4 was also
  associated with aggressive pattern of disease and
  with a shorter survival Eunhee et al. Mol Pathol
  1997
• C-erbB-3 was found to be overexpressed in
  squamous cell carcinoma, and its level of
  expression was higher in metastatic nodules than
  in the primary tumor tumor Funayama et al.
  Oncology 1998

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C-erbB-4 in NSCLC Aim of Study

• Evaluation of the expression of c-erbB-4 receptor
  in non-small cell lung cancer
• Correlation with the response to
  gemcitabine-cisplatin combination chemotherapy.

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C-erbB-4 in NSCLC Evaluation

• Anti-c-erbB-4 antibodies produced diffuse
  cytoplasmic brown granular staining in the tumor
  cells.
• Normal lung parenchyma (not bronchial tissue)
  displayed no detectable immunoreactivity.
• In the samples in which c-erbB4 was detected, a
  homogeneous pattern of staining was observed
  throughout the tumor.
• Weak or negative cytoplasmic staining was present
  in less than 60 of all cases.
• More than 40 of all the tumors showed moderate
  or strong immunostaining indicating
  overexpression of the receptor.

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C-erbB-4 in NSCLC Evaluation

• Weak / negative staining was detected in 91 of
  LN-negative tumors (less aggressive tumors?)
• Strong / moderate staining was found in 52 of
  the LN-positive tumors (2 degrees of virulence?)
• C-erbB4 expression was related to survival.
  Patient with high C-erbB4 expression had a
  significantly shorter survival. (22 months Vs.
  30 months plt0.05).
• A. Staroselsky, personal communication.

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C-erbB-4 in NSCLC Evaluation

• No correlation of c-erbB-4 expression with tumor
  type (pNS)

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C-erbB-4 in NSCLC Evaluation

• No correlation of c-erbB-4 expression with tumor
  grade (pNS)

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C-erbB-4 in NSCLC Aim of Study

• Evaluation of the expression of c-erbB-4 receptor
  in non-small cell lung cancer
• Correlation with the response to
  gemcitabine-cisplatin combination chemotherapy.

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Protocol Gemcitabine Cisplatin Combination

• Outpatient regimen
• Cisplatin 30 mg/m2/d on days 1 - 3
• Gemcitabine 1250 mg/m2/d on d1,8,15
• Repeat every 4 weeks
• Antiemetics Hydration Diuretics
• 2-3 courses were given until first evaluation
  objective subjective (CBR)

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Patients

• 43 pts (F14, M29) Age range 26-78 years
  (median 64)
• Histologically (20 pts) or cytologically (23 pts)
  proven.
• Adeno 35 SqCC 60 Bronch-Alveolar 5
• Stage IIIB 10/43 pts, IV 33/43 pts
• All the patients were chemonaive
• Numerous medical problems were recorded in 75
  of the patients (CVS, Respiratory)
• 95 of the patients were symptomatic
• KPS 50 to 90 (median 75)

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Immunohistochemistry

• Paraffin blocks from 20 patients with recurrent
  or advanced disease (Thoracotomy PCBx)
• When the diagnoses was based on BW or FNA (23/43
  cases), the material was insufficient for further
  stains.
• Immunohistochemical stains were performed on
  paraffin sections using the avidin-biotin-peroxida
  se method as described by Harpole et al. Harpole
  et al. Cancer Res 1995.

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Results (1) Treatment

• RR 42 CR 5 PR 37
• Disease-Control Rate RR MR 16 SD 7 65
• The TTP 0-69 weeks (median 18 weeks)
• The overall survival 4 to 98 weeks (median 45)
• There was no major difference between the
  response of stage IIIB to stage IV patients.
  Merimsky et al. Anti-Cancer Drugs
  200011117-121

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Results (2) c-erbB-4

• Expression of c-erbB-4 was
• positive in 5/20 pts.
• negative in 15/20 pts.
• Response to chemotherapy
• c-erbB-4 positive RR0/5
• c-erbB-4 negative RR (CR,PR) 8/15 (53)
• The negative stain for c-erbB-4 significantly
  favored response to GC (p0.02)
• No correlation between the staining and OS

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Comments Possible Implications

• Prognostication of NSCLC
• Prediction of response to GC combination
• Tailoring of chemotherapy according to cellular
  markers
• Avoiding unnecessary toxicity in positive
  c-erbB-4 patients
• Increasing the response and CBR of GC to 70
  (c-erbB-4 negative)
• Targeting of c-erbB-4 by MoAb

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Comments Caution !

• C-erbB-4 expression status showed no correlation
  with survival and cannot be accepted at this time
  as a guiding factor for therapeutic management.
• A large-scale prospective trial should be carried
  out before any recommendation on the basis of
  c-erbB-4 expression can be made.
• A multivariate analysis based on the expression
  of c-erbB-4 and other newly characterized
  molecules and gene transcripts may contribute to
  the accuracy of the trial.