1. Personalized Medicine: Can a non-profit public organization afford it – and for what purpose ? Nicky Liebermann MD, Head – Community Medicine Division ShmuelKlang PHD, Head – Pharmacology and Pharmacy Clalit Health Services

2. February 13, 2006: ‘Clalit Health Services’ will fund the most advanced test for breast cancer patients that will determine if they require chemotherapy. The test, called 'Oncotype DX', allows identifying which patients will benefit from a chemotherapy treatment, and which patients can be spared this harsh treatment. A breakthrough and news for breast cancer patients:

3. Why ??? The Israeli medical insurance system – National health law 4 HMO’s as service and insurance givers COMPETITION !!!! Every quarter any ensuree can change HMO Fixed basal basket of services Fixed payments (by the state) So we can compete only on quality, service and innovation

4. Why In Israel, polls found that women lead the family and its decisions in the fields of education and health. So the woman will chose the physician, the HMO/health plan etc. OncotypeDX-Breast presented the opportunity to tell breast cancer patients, with a sound level of certainty that after the surgery they are probably healthy !!!

5. Last why A wide psychological gap exists between the definition of a cancer patient, and a “cured” one. This impacts the health status of the whole family, it’s life style, it’s spirit. Clalit decided to invest the needed amount in order to offer it’s customers this product and by it to try and promote the general and personal health status of these families.

6. The process Oncologists cooperation – Imperative !!!! Accepted guidelines/protocol Medical and economical survey and sharing of the DATA with the clinicians The decision was to introduce the new technology for Clalit’s ensurees – accompanied by a common research with the company and the oncologists

7. Method The medical division developed assigned form for OncotypeDX Breast approval. The form contains the following information: Tumor size and biological markers The treatment the patient would have received without OnctoypeDX Breast assay The treatment the patient would receive for each Recurrence Score range – INTENTION TO TREAT Finally, based on Clalit database the patients’ actual treatment was reviewed.

8. Analysis Comparing the proposed treatment the patient would have received without OncotypeDX Breast with the actual, post OncotypeDX treatment (Intention to treat vs final decision) Comparison with the pre-written treatment according to the future RS range with the actual treatment

9. Clalit leads the OncotypeDX breast assays performed annually in Israel

10. Clalit leads the OncotypeDX breast assays performed annually in Israel for Node + breast cancer patients

11. First change in the protocol was to approve the test for node+ cases – long before it was accepted by others.

12. Treatment Recommendation before and after OncotypeDX Breast testing(N=313)

13. Chemotherapy by Risk Level

14. Average Added Cost (Saving) Per Patient Average added cost$1828 Oncotype Recurrence costs Supportive care Chemotherapy Adverse events

15. Economical and Clinical Applications The use of OncotypeDX Breast assay changed the treatment recommendation in 40% of the cases 84% Shifted from hormonal therapy+ chemo to hormonal therapy only. 8% of high risk patients by RS shifted from hormonal therapy to hormonal +chemo. The assay cost was partially funded by saving the chemotherapy and side effects related treatment costs.

16. The quality-adjusted life year (QALY) is a measure of disease burden, including both the quality and the quantity of life lived. Shifting from combination Chemo+Hormonal therapy to Hormonal therapy only = side effect prevention and better health status. Preventing disease recurrence for some of the patients found to be high risk by the assay. QALYs Gain

17. Cost-effectiveness ratio The QALY is based on the number of years of life that would be added by the intervention. Each year in perfect health is assigned the value of 1.0 down to a value of 0.0 for death. Cost with Oncotype DX – Cost without Oncotype DX QALYs with Oncotype DX – QALYs without Oncotype DX $1,828 = $10,770 per QALY gained 0.170 QALYs

18. NEJM: 2005: 353(14):1516-1521

21. Conclusion – Oncotype DX resulted in net QALY gain and increased overall costs, with an incremental cost effectiveness ratio of 10,770 $ per QALY gained. Oncotype DX represents an effective and affordable approach to favorably affect the lives of women with ESBC.

22. OncotypeDX breast N+ poster at ASCO 2010

23. OncotypeDX was used primarily in patients with micro-metastases, and 1 positive node (84% of patient population). Treatment decisions in these node-positive breast cancer patients was influenced primarily by the RS results and then by the nodal status. Patients with Nmic and RS<31 received less chemotherapy than patients with N1-3 and RS<31. All patients with RS>31 received adjuvant chemotherapy. OncotypeDX breast N+ poster at ASCO 2010- main points

24. Ongoing studies of Clalit with OncotypeDX breast Comparing treatment decision in N+ cases with RS data vs. matching control cases not analyzed for RS. Comparing the real recurrences vs. RS in the Clalit database of over 3,000 cases. ER, PR, HER2 status by IHC compared with that in RT-PCR by OncotypeDX. Evaluation of the RS predictive value by clinico-pathological factors.

26. Who is in the high risk group? Stage II colorectal patients Low Risk patients High Risk patients 30-50% ? 50-70% ? 1. Perforation 94-95% 5y survival 2. Lympho-vascular involvement 3.Perineural invasion 4. Preoperative CEA 5. Obstruction 6. < 10-12 lymph nodes examined 7. Poor Tumor differentiation 8. T4 9. Tumor budding DFS =4%, OS 1-2% (NS)

28. Profiles & Biomarkers Used in Clalit OncotypeDX Breast: Early breast cancer OncotypeDX Colon: Stage II colon cancer miRview mets: Carcinoma unknown primary K-RAS: Metastatic colon cancer EGFR: Non small cell lung cancer

29. Conclusions 1 Although “money makes the world go around”, there are other values to gain by implementing this new technology – better medical quality & accuracy, better quality of life for the patients & families, and, may be, with the improvement in the technology of “directing therapy” – targeted medicine, that will be even cost efficient because inefficient treatments will be avoided.

30. Conclusions 2 Implementation of a new technology should be supported by – Agreement/acceptance of the profession Defined/accepted protocol of use Registered follow up of cases Sharing the results with the clinicians

31. Thank you