RUOLO DELLA TERAPIA ANTIANGIOGENICA NEL CARCINOMA MAMMARIO Indicatori biologici di risposta

1. RUOLO DELLA TERAPIA ANTIANGIOGENICANEL CARCINOMA MAMMARIOIndicatori biologici di risposta Paolo Marchetti 1

2. Inhibition of Angiogenesis for Anti-Cancer Purposes 2 • Angiogenesis is a key process to tumor growth, and a limited process in healthy adults • Resistance to anti-angiogenesis drugs is also unlikely to occur, or at least at a much lower rate than seen with traditional cytotoxic chemotherapeutics, particularly if the genetically stable endothelial cells are targeted • While physiologic angiogenesis is a tightly orchestrated process that is regulated by a balance of pro- and anti-angiogenic factors, tumor angiogenesis is erratic and irregular, with leaky vessels that are poorly formed Kristina M. Cook and William D. Figg, CA Cancer J Clin. 2010

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4. Types of Biomarkers forAntiangiogenic Therapy in Cancer • Predictive • Prognostic • Pharmacologic • Response/Resistance • Safety • Surrogate

5. Evidence of Need for Biomarkers:Variability of Response • Same symptoms • Same findings • Same disease • Same drug...... Eric Van Cutsem & Donald McDonald, Prime Oncology 2010

6. Evidence of Need for Biomarkers:Variability of Response • Same symptoms • Same findings • Same disease • Same drug...... • ...Different effects • Variability of disease • Drug metabolism • Drug-drug interactions • Noncompliance Eric Van Cutsem & Donald McDonald, Prime Oncology 2010

7. Angiogenesis InhibitionResponse Biomarkers • The complex molecular pathways that govern tumor angiogenesis are logical targets for pharmacological manipulation given the important role they play in the growth and development of cancers • A lack of validated biomarkers and patient screening restricts our ability to tailor specific drugs to patient cohorts, and might be seen as one of the largest barriers to success in angiogenesis inhibition Kristina M. Cook and William D. Figg, CA Cancer J Clin. 2010

8. Eric Van Cutsem & Donald McDonald, Prime Oncology 2010

9. Antiangiogenic Biomarkers Are Centered on VEGF Pathway

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11. Pathways and mechanisms that can lead to increased angiogenesis Maria Alsina and Coll, 2010

12. Pathways and mechanisms that can lead to increased angiogenesis

13. Biomarkers:For the Tumor or for the Agent?

14. Biomarkers:For the Tumor or for the Agent? • How and where to look for biomarkers • Tumor imaging • Tumor histopathology • Tumor DNA/RNA/protein expression • Tumor mutations • Host polymorphisms • Blood chemistry, tumor cells, immune cells • Urine Eric Van Cutsem & Donald McDonald, Prime Oncology 2010

15. Key Anti-VEGF Biomarkers • VCAM-1 • MVD • PlGF • bFGF • ICAM • EGF • VEGF • CECs • E-selectin • VEGFR-2 • Polymorphisms • CD31 bFGF, basic fibroblast growth factors; CEC, circulating endothelial cell; EGF, epidermal growth factor; MVD, microvesseldensity; PlCF, placental growth factor; NSCLC, non-small cell lung cancer; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor

16. Biomarker Complexity:Primary Tumor vs Metastases

18. A Look Forward: What Type of Biomarkers Will Be Most Useful in Antiangiogenic Therapy? • SNPs • Imaging • Circulating tumor cells • Clinical Biomarkers

19. SNPs in the VEGF Pathway

20. Genetic and Proteomic Biomarkers

21. A Look Forward: What Type of Biomarkers Will Be Most Useful in Antiangiogenic Therapy? • SNPs • Imaging (dynamic contrast-enhanced (DCE)-MRI, DCE perfusion CT, PET): • Especially useful for the development of new agents • Goal: Integrate imaging with molecular markers • Drawbacks: Must treat patient first; therefore, not completely predictive • Circulating tumor cells • Clinical Biomarkers

22. A Look Forward: What Type of Biomarkers Will Be Most Useful in Antiangiogenic Therapy? • SNPs • Imaging • Circulating tumor cells • Surrogate marker • Reflective of vascular biology • Early data as predictive marker • Clinical Biomarkers

23. A Look Forward: What Type of Biomarkers Will Be Most Useful in Antiangiogenic Therapy? • SNPs • Imaging • Circulating tumor cells • Clinical Biomarkers • Hypertension

24. Angiogenesis BiomarkersKey Messages • Making progress • Starting to understand tumor biology • Clinical need for markers due to increase in treatment options • Entering a new era of predictive markers for antiangiogenic therapy • Increasing awareness that collaboration is necessary for marker development • Integration of marker types key for future Eric Van Cutsem & Donald McDonald, Prime Oncology 2010

25. Conclusions • The possible role of biomarkers in better selecting patients who would derive the greatest benefit from the antiangiogenic therapy has not been taken into account in approving antiangiogenic drugs for cancer management. • These biomarkers might be useful for monitoring angiogenesis, assessing drug activity and distinguishing between effective and noneffective drugs that predict clinical outcome and response to therapy, defining the optimum biological dose, facilitating development of combination therapies, and rapidly identifying resistance to treatment. Maria Alsina and Coll, 2010

26. Conclusions • However, no validated biomarkers of angiogenic or antiangiogenic activity are available for routine clinical use • Advances in this field will facilitate the integration of biomarkers with functional and clinical data in the selection of treatment • It is hoped these prognostic and predictive factors will be integrated, at some time point, in the treatment algorithms Maria Alsina and Coll, 2010