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
Stage of Lung Cancer at Diagnosis- SEER Data
18%18%
39%25%
1
23
4
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.
Schiller JH. NEJM 2002; 346:92-98
Chemotherapy Doublets for Lung Cancer Treatment
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
Lung Cancer Chemotherapy
• Future of lung cancer chemotherapy– Get better drugs
• There is some benefit from current drugs– Individualize treatment for patients
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.
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
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
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
Lung Tumors: Cluster All Probes22,000 Genes Significantly Changed
337
Tumors
Normals
Keratin Expression in 337 Lung Tumors
337Tumors
Keratins
Krt5/6, 14/16 Positive Lung Tumors
37 tumors(11%)
Squamous Lung Tumors on Cluster
337
Tumors Agilent 44K Chip
Neuroendocrine Tumors on Cluster
337
Tumors Agilent 44K Chip
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
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
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
Lung Mass
Diagnostic Biopsy
Surgery
Appropriate Additional Therapy
Appropriate Follow-Up
Assess Response to any Further
Therapy
5-11 days of drug
Clinical Trial
• Evaluate molecular changes with chemo
• Evaluate changes in cell metabolism with chemo
Future of Lung Cancer Chemo
• Individualize treatment based upon a patient’s tumor markers or gene analysis