1. PET/CT Imaging and Cancer Response to Treatment Dr. François Bénard

2. Potential Conflict of Interest None

3. PET/CT imaging and cancer response to treatment François Bénard, MD, FRCPC BC Cancer Agency

4. Cancer Resistance Increased efflux of drug (P-glycoprotein and others) Decreased influx/transport Altered or absent binding sites Enzymatic inactivation Alternate growth pathways

5. Why use surrogate measures of tumour response? Ultimate goal (enhanced patient survival, quality of life, reduced costs) are appropriate endpoints for phase 3 trials Phase 2 trials need intermediate endpoints to speed up drug discovery and reduce trial costs Rapidly identify ineffective treatments Speed up the identification of resistance and target patients with sensitive or resistance phenotypes to identify causes (host-related, tumour related)

6. Treatment response biomarkers Plasma or urine proteins (PSA, CA 15.3, CA 125, CEA) Circulating tumour cells Metabolomics profiles (urine, plasma) Histopathology/immunofluorescence (biopsies) Imaging methods –Conventional (morphological: CT, MRI, US) –Functional DCE/Diffusion MRI Perfusion CT Nuclear Medicine / PET Optical (surface imaging)

7. Conventional Tumor Response Assessment Usually performed using cross sectional imaging WHO criteria replaced with RECIST criteria Modified RECIST criteria published 2009 Morphological measurements of solid tumours Assessment at least 8 weeks from treatment initiation

8. RECIST 1.1 Requires a measurable lesion –Size 10 mm (CT, caliper) to 20 mm (Chest X- ray) –Enlarged lymph node > 15 mm in short axis –Non-measurable: < 10 mm (or nodes 10-15 mm short axis), leptomeningeal, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement skin/lung, most bone metastases, previously irradiated fields, cystic lesions

9. RECIST 1.1 Up to 5 measurable lesions Maximum of 2 lesions per organ Selected by size (longest diameter) Lymph node size measured on shortest diameter Sum of the diameters of lesions (longest for non-nodal, shortest for nodes)

10. Treatment response prediction vs measurement Prediction –A test to predict response to treatment before it is administered –Typically predicts sensitivity of a tumour to respond to treatment –Classical examples: ER and HER2/neu in breast cancer Response measurement –Measurement of tumor sensitivity after onset of treatment –Biomarkers or imaging –Documents treatment resistance

11. Limitations of planar measurements Delay in identifying resistance Not adapted to evaluate cytostatic rather than cytotoxic treatments (progressive disease remains progressive disease even if tumor growth is slowed) May not identify the appearance of treatment resistant clones Not suitable for bone metastases or when no measurable lesion is available Residual fibrotic/necrotic masses

12. Functional Imaging in Cancer Response Assessment Conventional Nuclear Medicine –Bone scintigraphy and some receptor binding agents –Currently qualitative –Flare phenomena Contrast-enhanced CT –Perfusion CT –Density/enhancement signal changes Dynamic contrast-enhanced MRI / Diffusion imaging Positron emission tomography with CT

13. PET imaging 101

14. Treatment response to imatinib Before treatment 1 month after imatinib initiation Van Den Abbeele AD, The Oncologist 2008; 13: 8-13

15. Large B-cell lymphoma: Baseline

16. Large B-cell lymphoma: After 1 cycle

17. Baseline 1 cycle 4 cycles Rapid response assessment to therapy

18. Baseline 1 cycle 4 cycles Rapid response assessment to therapy

20. False Positive Residual Mass Non seminomatous GCT Before chemotherapy GCT with bulky mets After chemotherapy Mild-moderate residual uptake After surgery Path: granulomatous inflammation

21. Recurrent Ovarian Cancer 12/98 03/99 01/00 09/00

22. Assessment of treatment response

23. Treatment Response Assessment in Breast Cancer 02/2002 06/2002 Lack of treatment response documented by PET after chemotherapy

24. Timing of the treatment response Couturier O et al., Clin Canc Res 2006; 12:6437-6443

25. Predictive value of FDG-PET 21 days after cycle 1 21 days after cycle 3 Couturier O et al., Clin Canc Res 2006; 12:6437-6443

26. From: Wester, HJ. Nuclear Imaging Probes: from Bench to Bedside. Clin Cancer Res 2007;13(12): 3470-3481 Radiotracers of interest in oncology

27. A v β 3 integrin imaging with 18 F-RGD to predict/monitor anti-VEGF therapy Beer AJ et al., J Nucl Med 2008; 49:22-29.

28. Estrogen Receptor Imaging in Metastatic Breast Cancer FDG FES

29. Measuring response to hormone therapy Baseline After 2 months (aromatase inhibitor)

30. PRECLINICAL MICRO PET/CT IMAGES

31. Using 18 F-FDG PET to monitor treatment response

32. Early response and flare reaction

33. Estrogen challenge to predict resistance to hormone therapy Baseline FDG-PET Repeated after 3 x 10 mg doses of estradiol q 8-10h If increase in FDG uptake < 12% after estradiol administration, this was predictive of hormone therapy failure Dehdashti F et al., Breast Cancer Res Treat 2009; 113: 509-17

34. Role vs other predictors Tumor microarrays (DNA, RNA, microRNA) or IHC/FISH panels can provide information about expression of genes/proteins associated with resistance No « pattern » is entirely predictive Combining genetic predictors with rapid imaging assay of treatment failure could be a powerful way to identify resistance Rapidly select patients for phase II clinical trials or tissue banking

35. Increased Efflux P-glycoprotein substrates –[ 99m Tc]-Sestamibi –[ 11 C]-Verapamil –[ 11 C]-carvedilol –[ 11 C]N-Desmethyl-Loperamide –[ 11 C]daunorubicin –4-[ 18 F]Fluoropaclitaxel Common problem: low tumour uptake / constrast

36. Chemotherapy influx Can chemotherapy response be predicted by tracers with similar uptake mechanisms? Cationic organic transporters Anionic transporters Other ions?

37. Folate receptor mediated transport 99m Tc-EC20 Folate receptor scintigraphy. Fisher RE et al., J Nucl Med 2008; 49:899-906

38. Zr-89 Cetuximab Disparity between WB receptor expression and antibody uptake Aerts HJWL et al., J Nucl Med 2009; 50: 123-131

39. 18F-Labeled HER2-Affibody Kramer-Marek et al., Eur J Nucl Med Mol Imag 2008; 35:1008- 1018; NIH, Bethesda, MD

40. Conclusion PET/CT imaging offers unique new opportunities to predict or rapidly identify treatment resistance In vivo targeted imaging Radiopharmaceuticals to predict chemotherapy influx / efflux ? Possible role for combining predictive biomarkers (DNA/RNA microarrays) and early response imaging to identify resistance