2. Cedars Sinai Medical Center
Gene Expression Analysis for targeted Chemotherapy in Lung Cancer Patients PF
Robert J McKenna Jr. MD
Head, Thoracic Surgery
Cedars Sinai Medical Center

3. Stage of Lung Cancer at Diagnosis- SEER Data3 2 4 1

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.

6. Chemotherapy Doublets for Lung Cancer Treatment
Schiller JH. NEJM 2002; 346:92-98

7. 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

8. Lung Cancer Chemotherapy
Future of lung cancer chemotherapy
Get better drugs
There is some benefit from current drugs
Individualize treatment for patients

9. 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.

10. 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

11. AGILENT MICROARRAY PLATFORM
1. Pre treatment core vs tumor reference
2. Pre- vs post
3. Post-vs pre-
Fluor reversal
mRNAs
Cy3
Cy5
22,000 spots each containing a 60mer representing a known gene.
The two probes hybridize to the spots in proportion to concentration
of the specific RNA in each probe.

12. RNA extraction of Lung Tumors
RIN 9.0 S
RIN 9.3 S
RIN 9.4 S
RIN N/A

13. Lung Tumors: Cluster All Probes
22,000 Genes Significantly Changed 3 7 T u m o r s
Normals

14. Keratin Expression in 337 Lung Tumors
Keratins
337
Tumors

15. Krt5/6, 14/16 Positive Lung Tumors
(11%)

16. Squamous Lung Tumors on Cluster3 7 T u m o r s
Agilent 44K Chip

17. Neuroendocrine Tumors on Cluster3 7 T u m o r s
Agilent 44K Chip

18. 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

19. 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

20. 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

21. Appropriate Additional Therapy Appropriate Follow-Up
5-11 days of drug
Diagnostic Biopsy
Lung Mass
Surgery
Appropriate Additional Therapy
Assess Response to any Further Therapy
Appropriate Follow-Up

22. Clinical Trial Evaluate molecular changes with chemo
Evaluate changes in cell metabolism with chemo

23. Future of Lung Cancer Chemo
Individualize treatment based upon a patient’s tumor markers or gene analysis