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Intratumoral mRNA expression of genes involved in angiogenesis and HIF-1 pathway to predict outcome to VEGFR tyrosine kinase inhibitor (TKI) in patients.

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Presentation on theme: "Intratumoral mRNA expression of genes involved in angiogenesis and HIF-1 pathway to predict outcome to VEGFR tyrosine kinase inhibitor (TKI) in patients."— Presentation transcript:

1 Intratumoral mRNA expression of genes involved in angiogenesis and HIF-1 pathway to predict outcome to VEGFR tyrosine kinase inhibitor (TKI) in patients enrolled in CONFIRM1 and CONFIRM2 Peter M. Wilson, Ph.D. D. Yang, M. M. Shi, W. Zhang, C. Jacques, J. C. Barrett, K. Danenberg, T. Trarbach, G. Folprecht, G. Meinhardt, H. J. Lenz Department of Pathology and Division of Medical Oncology GI Oncology Program The Sharon E Carpenter Laboratory USC Norris Comprehensive Cancer Center USC Keck School of Medicine Los Angeles, CA.

2 Disclosures  Response Genetics  Novartis Pharmaceutical Corp  Bayer Schering Pharma

3 Background  Colorectal cancer is 3 rd most common cause of cancer in the US.  In 2008 there will be an estimated † :  149,000 cases  50,000 deaths  Prognosis depends on:  Stage  Patient performance status  Tumor differentiation  Molecular Markers (MSI, 18q status) † - American Cancer Society – Estimated New Cancer Cases and Deaths, US, 2008

4 CONFIRM Trials  PTK/ZK – Oral anti-angiogenic agent 1  Competitive inhibitor at the ATP-binding site of VEGF receptors 1-3, platelet-derived growth factor and c-kit. 1. Wood JM, Bold G, Buchdunger E, et al. Cancer Res, 2000; 60:2178-89.  Randomized, double-blind, placebo-controlled, phase III trials in patients with metastatic adenocarcinoma of the colon or rectum.

5 VEGFR-1 / Flt-1 VEGFR-2 / KDR VEGFR-3 / Flt-4 Angiogenesis Lymphangiogenesis Metastasis XX XX X X PTK/ZK VEGF-A VEGF-B PIGF VEGF-A VEGF-C VEGF-D VEGF-C VEGF-D PTK/ZK Inhibits All Known VEGF Receptors Extracellular Intracellular  Inhibition of angiogenic signals 1  Inhibition of metastasis  Sensitization to chemo- therapeutics 2 2. Sini P, Samarzija I, Baffert F, et al. Cancer Res 2008;68:1581-1592. Bevacizumab 1. Wood JM, Bold G, Buchdunger E, et al. Cancer Res, 2000; 60:2178-89.

6 CONFIRM Trials RandomizedRandomized FOLFOX4/PTK 585 Patients FOLFOX4/Placebo 583 Patients CONFIRM 1 1 ST Line 1168 Patients RandomizedRandomized FOLFOX4/PTK 429 Patients FOLFOX4/Placebo 426 Patients CONFIRM 2 2 ND Line 855 Patients Progressed from irinotecan-based therapy Stratification Factors  PS 0, 1-2  LDH ≤, > 1.5 x ULN ULN – Upper limit of normal; PS – Performance status; LDH – Lactate dehydrogenase

7 Response to PTK/ZK Overall Response Complete Response Partial Response Stable Disease Progressive Disease PTK/ZKPlacebo 46 47 19 18 4 5 2 1 42 43 17 17 32 32 42 43 FOLFOX4 + 17 17 34 37 CONFIRM1 CONFIRM2 PTK/ZKPlacebo

8 PFS and OS in CONFIRM1 Overall Survival High LDH Progression Free Survival High LDH Hecht et al. European Cancer Organization,2007  No statistically significant increase in PFS or OS in total population with PTK/ZK treatment

9 PFS and OS in CONFIRM2 Overall Survival High LDH Progression Free SurvivalProgression Free Survival High LDH Kohne et al. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S, 2007: 4033 Overall Survival

10 M Clinical Significance of LDH  Patients with high serum LDH appear to benefit most from PTK/ZK  Facilitates anaerobic glycolysis  Marker for increased tumor burden and aggressive disease  Associated with poor prognosis  LDH may be a surrogate marker for HIF- 1 signaling and proangiogenic propensity M M M LDHA Gene M LDH5 Enzyme Koukourakis et al. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 4107 Koukourakis et al. Journal of Clinical Oncology, 2006 Sep 10;24(26):4301-8. Koukourakis et al. Clin Exp Metastasis. 2005;22(1):25-30.

11 LDH Correlates with HIF1 Signaling  Serum LDH level was associated with activation of HIF-related intratumoral gene expression in 92 specimens from 36 mCRC patients Azuma et al. Pharmacogenomics. 2007 Dec;8(12):1705-13. VEGFR1 VEGFA Serum LDH p=0.006 p=0.004 mCRC – metastatic colorectal cancer HIF2α VEGF LDHA p=0.001 HIF1α Glut1 p=0.013 p=0.044 p=0.007 Intratumoral

12 Objectives  Identify a panel of molecular markers predicting outcome to PTK/ZK in patients enrolled in CONFIRM1 and CONFIRM2  To measure intratumoral mRNA expression of genes involved in:  Hypoxia  Glycolysis  Angiogenesis

13 HIF-1 Signaling Gene Expression Oncogene Signaling PI3K PKC RAS SRC HIF-1α Hypoxia Nucleus VEGF (angiogenesis) GLUT1 (glucose transport) LDH-A (glycolysis) EPO (erythropoiesis) VHL NOS ARNT HRE Normoxia VHL

14 Methods I  191 formalin-fixed paraffin-embedded tumor samples were obtained from CONFIRM 1 and 2. CONFIRM 1 85 Patients FOLFOX4/PTK 52 Patients FOLFOX4/Placebo 54 Patients CONFIRM 2 106 Patients FOLFOX4/PTK 43 Patients FOLFOX4/Placebo 42 Patients  Specimens obtained at time of diagnosis.

15 Patient Characteristics CONFIRM1 CONFIRM2 PTK/ZKPlacebo PTK/ZKPlacebo Characteristics (n=43)(n=42)(n=52)(n=54) Median age, y 63626462 Male/Female 31/1225/1734/1840/14 (72%/28%)(60%/40%)(65%/35%)(74%/26%) Low / High LDH 35/831/1136/1643/11 (81%/19%)(74%/26%)(69%/31%)(80%/20%) WHO PS, 0/1 or 2 23/2026/1625/2729/25 (53%/47%)(62%/38%)(48%/52%)(54%/46%) Patient characteristics for CONFIRM 1 and CONFIRM 2 are well balanced between treatment groups, all p-values >0.05

16 Methods II RNA Extracted Reverse Transcription PCR with TaqMan ® Data Analysis RNA cDNA Laser Capture Micro-dissection

17 Candidate Genes PTK/ZK HIF-1α Nucleus ANGIOGENESIS VEGF VEGFR 1/2 GLYCOLYSIS Glut1 HYPOXIA HIF1α LDHA Ability to predict outcome to PTK/ZK

18 Gene Expression Medians and Range CONFIRM1CONFIRM2 FOLFOX4+PTK/ZKFOLFOX4+PlaceboFOLFOX4+PTK/ZKFOLFOX4+Placebo Gene*NMedian (range)N N N LDHA421.11 (0.07-2.54)411.09 (0.14-3.63)520.91 (0.23-3.46)501.04 (0.20-2.66) Glut1422.11 (0.26-23.86)412.49 (0.36-38.59)512.39 (0.45-13.37)503.45 (0.50-35.48) HIF1a421.62 (0.59-3.68)411.62 (0.31-4.98)521.43 (0.60-6.45)501.43 (0.55-3.65) VEGF426.21 (3.05-21.90)415.79 (1.29-15.90)525.71 (2.32-35.33)507.57 (2.54-65.06) VEGFR1416.28 (0.49-23.25)365.59 (0.56-28.06)485.33 (1.53-20.62)406.15 (2.54-17.83) VEGFR2421.91 (0.02-8.16)411.64 (0.62-11.63)502.11 (0.76-10.46)501.95 (0.49-14.48) No significant differences between trials or treatment groups; all p-values >0.05

19 Response to PTK/ZK >LDHA 0.033 >Glut1 0.045 >VEGFR1 0.012 <HIF-1α 0.021 CONFIRM 1 Genep-valueGenep-value CONFIRM 2

20 Response to PTK/ZK 0% 10% 20% 30% 40% 50% 60% 70% 80% <0.36 >0.36<1.50>1.50 <3.78>3.78 Response Rate N Glut 1VEGFR1 LDHA 6 35 11 30 10 30 P = 0.033P = 0.045 P = 0.012 CONFIRM 1

21 Response to PTK/ZK CONFIRM2 0% 10% 20% 30% 40% 50% 60% <1.18 > 1.18 Response Rate N Hif1a 19 32 P = 0.021

22 Response to PTK/ZK VEGFR1 (n=42) <3.85 Group 1 (10%) ≥ 3.85 Group 3 (61%) Confirm 1 Hif1a (n=51) ≥1.21 <1.21 Group 2 (53%) Group 1 (13%) Confirm 2 Response (n=93) Multivariate Analysis: - Serum LDH - Age - Gender - Performance Status

23 PFS with PTK/ZK >HIF-1α 9.4 v 3.5 >LDHA 11.3 v 7.6 >VEGFR2 8 v 4.1 CONFIRM 1 GeneMonthsGene Months CONFIRM 2 <HIF-1α 7.6 v 2.7 <LDHA 7.6 v 1.7 0.075 0.021 0.031 0.001 P Value

24 VEGFR2 CONFIRM1 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0510152025303540 Months since randomization Estimated Probability of Progression-Free Survival P for interaction between treatment and VEGFR2 expression = 0.001 VEGFR2 <2.98 (n=34) with PTK/ZK VEGFR2 > 2.98 (n=8) with PTK/ZK VEGFR2 <2.98 (n=34) w/o PTK/ZK CONFIRM 1 VEGFR2 > 2.98 (n=7) w/o PTK/ZK

25 Confirm 2 Hif1a (n=52) <0.85 Glut1 (n=42) ≥3.25 ≥0.85 Group 3 HR=1.25 (n=10) Group 5 HR=7.96 (n=16) <3.25 Group 4 HR=3.02 (n=26) PFS with PTK/ZK PFS (n=95) LDHA (n=43) ≥ 0.92 Group 1 HR=1 (n=28) < 0.92 Group 2 HR=1.94 (n=49) Confirm 1 Multivariate Analysis: - Serum LDH - Age - Gender - Performance Status

26 Overall Survival with PTK/ZK <VEGFR2 0.012 CONFIRM 1 Genep-valueGenep-value CONFIRM 2 <Glut1 0.021

27 Confirm 2 Glut1 (n=52) < 3.28 Glut1 (n=36) ≥ 2.12< 2.12 ≥ 3.28 Group 5 HR=12.9 (n=16) Group 3 HR=2.00 (n=17) Group 4 HR=4.32 (n=19) OS in CONFIRM 1 and 2 Overall Survival (n=95) VEGFR2 (n=43) Confirm 1 < 1.78 Group 1 HR=1 (n=17) ≥ 1.78 Group 2 HR=2.49 (n=26) Multivariate Analysis: - Serum LDH - Age - Gender - Performance Status

28 VEGFR2 Predicts OS in CONFIRM1 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0612182430364248 Months since randomization Estimated Probability of Survival AdjustedP value = 0.012 VEGFR2 < 1.76 (n=38) VEGFR2 > 1.76 (n=45) CONFIRM 1 VEGFR2 >1.76 35.8 mo v 20 mo

29 Conclusions  Genes involved in HIF-1α and angiogenesis pathway are associated with response and PFS with VEGFR TKI treatment.  These molecular markers were independent of serum LDH.  Genes in this pathway (VEGFR2) may have prognostic value for overall survival.  Provides an initial panel of markers which warrant further testing in clinical trials with future VEGFR TKIs.

30 Acknowledgements The patients and their families and Investigators who participated in CONFIRM 1 and 2. Response Genetics:Kathleen D. Danenberg. USC Statistics: Dongyun Yang. Novartis / Bayer Schering AG CONFIRM team: Michael M. Shi, Christian Jacques, J. Carl Barrett, Bee Chen and Gerold Meinhardt. Funding: Dhont Foundation and Carpenter Lab

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