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Reduced Tumour RNA Integrity in Response to Chemotherapy in Breast Cancer Patients

Reduced Tumour RNA Integrity in Response to Chemotherapy in Breast Cancer Patients . Northern Health Research Conference May 28, 2010 Sudbury, ON. Disclosure Statement.

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Reduced Tumour RNA Integrity in Response to Chemotherapy in Breast Cancer Patients

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  1. Reduced Tumour RNA Integrityin Response to Chemotherapy in Breast Cancer Patients Northern Health Research Conference May 28, 2010 Sudbury, ON

  2. Disclosure Statement • Patents related to the findings presented in this seminar have been filed and are entering the national phase in Canada, the U.S.A., Europe, Australia, and Japan • A company (RNA Diagnostics, Inc.) will commercialize the intellectual properties associated with the patent, for which I am a shareholder and serve as its Chief Scientific Officer

  3. Locally Advanced Breast Cancer • A breast cancer that has progressed locally but has not yet spread outside the breast and local lymph nodes • Includes large breast tumors (more than 5 centimeters in diameter), those that involve the skin of the breast or the underlying muscles of the chest wall, and cancers that have extensive involvement of the local lymph nodes (in the axilla or in the soft tissues above and below the collarbone) • Also includes inflammatory breast cancer, a rapidly growing type of cancer that makes the breast appear red and swollen, without a distinctive breast lump

  4. Treatment of Locally Advanced Breast Cancer • For most women with locally advanced breast cancer, chemotherapy is the first component of the treatment, before surgery (aka “neoadjuvant chemotherapy”) • Typically, patient tumours are treated with an anthracycline (doxorubicin or epirubicin) in concert or followed by a taxane (paclitaxel or docetaxel) • In some countries pre-operative chemotherapy has become standard for treatment of most breast cancers, since survival rates appear to be similar if chemotherapy precedes surgery

  5. Typical Response Rates for Treatment of Locally Advanced Breast Cancer by Chemotherapy • Typically ~30% of patients with locally advanced breast cancer have a clinical complete response to neoadjuvant chemotherapy (complete disappearance of all detectable malignant disease in breast by palpation) • In contrast, only ~10% of patients with locally advanced breast cancer have a pathologic complete response to neoadjuvant chemotherapy (complete eradication of disease at the cellular level)

  6. Utility of a Biomarker of Response to Chemotherapy • The low rates of clinical complete response and pathologic complete response in patients with inflammatory breast cancer indicate that vast majority of these patients will experience disease recurrence and/or progression of disease • Thus, it would be highly useful to be able to monitor response to chemotherapy in inflammatory breast cancer patients • If tumours show a lack of response to chemotherapy, then chemotherapy (and its side effects) can be discontinued and downstream options such as surgery, radiation therapy, or other chemotherapy drugs could be quickly considered

  7. Tumour RNA Quality (Integrity) as a Biomarker of Chemotherapy Response • Unlike DNA, RNA is much less stable in normal and tumour cells • Recent evidence suggests that chemotherapy agents may induce RNA damage and the production of RNA-degrading enzymes • It is possible that a reduction in tumour RNA integrity could serve as a useful biomarker of chemotherapy response in patients with inflammatory breast cancer.

  8. The RNA Integrity Number (RIN): A quantitative measure of RNA quality, not quantity

  9. NCIC-CTG MA.22 Clinical Trial • Patients with locally advanced breast cancer are typically treated with anthracyclines followed by taxanes Popular Regimens:AC→T, EC →T, FEC 100 →T (all q3wX6) • However, <40% of patients respond to taxanes after anthracycline-based chemotherapy • MA.22 is assessing whether anthracycline/taxane chemotherapy may have greater therapeutic efficacy if the drugs are co-administered rather than given sequentially

  10. Tumour RIN Values of 50 MA.22 Patients (Pre-, Mid-, And Post-Treatment) Dose Level 1 Dose Level 2 Dose Level 3 Dose Level 4 Dose Level 5 Dose Level 6 Dose Level 7 (p=0.12) (p=0.05) P-value from one-way Analysis of Variance (ANOVA)

  11. Relationship Between Tumour RIN and Tumour Cellularity (Extent)

  12. Plot of Tumour RIN Versus Tumour Cellularity (Extent) for Each Patient in the MA.22 Clinical Trial Tumour RIN is NOT a surrogate measure of tumour cellularity

  13. RIN and Tumor Cellularity by Response to Clinical Treatment 1P-value from one-way Analysis of Variance (ANOVA). • Correlation between low mid-treatment tumour RIN values and drug dose level • suggests that tumour RIN may clearly be a biomarker of drug response • Data suggests that mid-treatment tumour RIN determinations can predict post- • treatment pathologic complete response • Pathologist cannot predict whether patient will undergo pathologic • complete response by examining tumour cellularity mid-treatment

  14. Future Perspectives Related to theUse of the RIN as a Biomarkerof Chemotherapy Response – Part I • We have heard that Dr. John Bartlett of the University of Edinburgh in the UK has validated our findings in an independent cohort of breast cancer patients treated with an anthracycline-based chemotherapy regimen • Our findings will hopefully be further validated in an additional independent cohort of breast cancer patients treated with various chemotherapy regimens in collaboration with I-Spy Clinical Trial in the U.S.A. • The I-SPY trial will also assess how soon after treatment statistically significant reductions in tumour RIN can be observed, which predict pathologic complete response in cancer patients

  15. Future Perspectives Related to theUse of the RIN as a Biomarkerof Chemotherapy Response – Part II • Future studies will also focus on determining whether similar reductions in tumour RIN can be observed in patients with other solid and nonsolid tumours that are being treated with a variety of chemotherapy drug classes • A new company (RNA Diagnostics, Inc.), Inc. has negotiated an exclusive license to the IP associated with the patent. It will fund further validation studies and productize what we are calling the “RNA Disruption Assay” or RDA for measuring chemotherapy response in cancer patients.

  16. A New Research Grant! • The Cancer Research Fund of the Ontario Institute for Cancer Research has awarded a $381,847 grant to further these promising studies • Principal Investigator: Dr. A. Parissenti of NOSM/LU/SRH • Co-investigators • Dr. D. Maclean, graduate student S. Fabris, animal studies • Dr. M. Trudeau, Sunnybrook Hospital, MA.22 clinical trial • Dr. L. Esserman, UCSF San Francisco, I-SPY clinical trial • Drs. L. Shepherd, J. Chapman, NCIC Clinical Trials Group

  17. Acknowledgements Judy-Anne W. Chapman2, Harriette J. Kahn3, Baoqing Guo1, Lei Han2, Patti O’Brien2, Mark P. Clemons4, Roberta Jong3, Rebecca Dent3, Barbara Fitzgerald4, Kathleen I. Pritchard3, Lois E. Shepherd2, Stacey Santi1, and Maureen E. Trudeau3 1Regional Cancer Program, Sudbury Regional Hospital, Sudbury, ON, 2National Cancer Institute of Canada Clinical Trials Group, Queen’s University, Kingston, ON, 3TorontoSunnybrook Health Sciences Centre, Toronto, ON, 4Princess Margaret Hospital, University Health Network, Toronto, ON

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