gene expression analysis for targeted chemotherapy in lung cancer patients pf-00299804 robert j...
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Gene Expression Analysis for targeted Chemotherapy in
Lung Cancer PatientsPF-00299804
Gene Expression Analysis for targeted Chemotherapy in
Lung Cancer PatientsPF-00299804
Robert J McKenna Jr. MDRobert J McKenna Jr. MD
Head, Thoracic SurgeryHead, Thoracic Surgery
Cedars Sinai Medical CenterCedars Sinai Medical Center
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Stage of Lung Cancer at Diagnosis- SEER Data
18%18%
39%25%
1
23
4
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Adjuvant Chemotherapy
• No clear supportive data in Stage 1
• Benefit seen in tumors greater than 4 cm
• Statistically significant benefit in Stage II and Stage IIIA
• Benefit all with cis-platin based chemo.
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Schiller JH. NEJM 2002; 346:92-98
Chemotherapy Doublets for Lung Cancer Treatment
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Lung Cancer Chemotherapy
• Overall, any doublets have about a 40% response rate– That means 60% chemo given has no clinical
response
• Adjuvant treatment increases survival 5-10%– That means 90% given with no change in
survival
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Lung Cancer Chemotherapy
• Future of lung cancer chemotherapy– Get better drugs
• There is some benefit from current drugs– Individualize treatment for patients
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EGFR Inhibition• The epidermal growth factor receptor is
on the surface of cells. It transmits signals to the cell, including to grow and divide.
• Erlotinib has shown benefit in NSCLC.
• Overall magnitude of the benefit is small.
• Magnitude of benefit in responders is high.
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Primary Tumor Work
• Tissue is obtained
• RNA is evaluated in the laboratory to ensure samples are of high quality
• Microarray analysis is performed using the Agilent system
• Molecular data is correlated with clinical data and patient outcome
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Cy3
Cy5
22,000 spots each containing a 60mer representing a known gene.The two probes hybridize to the spots in proportion to concentrationof the specific RNA in each probe.
mRNAs
AGILENT MICROARRAY PLATFORM1. Pre treatment core vs tumor reference2. Pre- vs post3. Post-vs pre-
Fluor reversal
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RNA extraction of Lung Tumors
S-06-38515 RIN 9.3
S-06-39372 RIN 9.0
S-06-38568 RIN 9.4
S-07-00211 RIN N/A
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Lung Tumors: Cluster All Probes22,000 Genes Significantly Changed
337
Tumors
Normals
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Keratin Expression in 337 Lung Tumors
337Tumors
Keratins
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Krt5/6, 14/16 Positive Lung Tumors
37 tumors(11%)
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Squamous Lung Tumors on Cluster
337
Tumors Agilent 44K Chip
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Neuroendocrine Tumors on Cluster
337
Tumors Agilent 44K Chip
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Conclusions from primary samples
• High quality RNA has been obtained from nearly all of the samples
• Clear molecular subtypes can be found
• Data correlating gene expression with patient outcome will be available soon
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Cell Line Collaboration
• We are evaluating novel compounds in a panel of 60 NSCLC cell lines
• Correlate cell line data with the data from primary tissue
• For a pre-surgical study, we selected the irreversible pan-HER inhibitor PF-299804
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Clinical Trial
• A presurgical study to evaluate molecular changes that occur in human non-small cell lung cancer tissue after short term exposure to PF-00299804
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Lung Mass
Diagnostic Biopsy
Surgery
Appropriate Additional Therapy
Appropriate Follow-Up
Assess Response to any Further
Therapy
5-11 days of drug
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Clinical Trial
• Evaluate molecular changes with chemo
• Evaluate changes in cell metabolism with chemo
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Future of Lung Cancer Chemo
• Individualize treatment based upon a patient’s tumor markers or gene analysis
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