Genetic Predictors of Radiosensitivity.

Transcription

1 Genetic Predictors of Radiosensitivity. Richard G. Stock, MD Professor, Director of Genito-Urinary Oncology Department of Radiation Oncology Ichan School of Medicine at Mount Sinai New York, NY

2 DISCLOSURE n No real or apparent financial relationship to disclose related to the topic of this activity.

3 Genetic Testing Predictive of Prostate Cancer Risk. NEJM - Feb 28, 2008

4 Genetic Testing Predictive of Prostate Cancer Risk. n Risk Ratio s of 16 tested SNPs were between 1.07 and 1.65 n If one adds family history, age and five of five selected at-risk SNP s the RR is This applied to 1.4% of the population. Comment by Edward P. Gelmann, NEJM - Feb 28, 2008

5 Genetic Testing Predictive of Prostate Cancer Risk. n If a positive family history and 4 of 5 SNPs are positive then the RR is 4.5. n This applied to 5.4% of the men with prostate cancer and 2.2% of the controls. n No association was found with cancer aggressiveness. Comment by Edward P. Gelmann, NEJM - Feb 28, 2008

6 There is a well known genetic basis for normal tissue radiosensitivity. American Journal of Diseases of Children (1968) 116: 392

7 Radiation Mechanism 1.)Physical Interaction n Radiation ionizes molecules in human cells. DNA has been known for some time to be the primary target.

8 Radiation Mechanism 2.) Biological Interaction n It is biologically and physically predictable. (there is a target and a measurable dose-volume effect) n Specialty Techniques and Outcomes should be reproducible from one facility to the next. n Regardless unpredictable side effect do manifest.

9 The Number and Type of Ionizing Radiation Induced Lesions in DNA per Gray/per Cell! TYPE OF LESION NUMBER /Gy /diploid cell double strand break single strand break base damage sugar damage DNA-DNA crosslinks DNA-protein crosslinks

10 Our Molecular DNA Repair Mechanisms are Extremely Effective and Efficient Though Not Always Successful. DNA DAMAGE RESPONSE ACCURATE REPAIR MIS-REPAIR FAILED REPAIR SURVIVAL GENETIC MUTATION DEATH DYSFUNCTION

11 There are two approaches to finding candidate genes in order predict sideeffects prior to radiotherapy 1. Theoretical. 2. Practical. Shiloh Y. ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer Mar;3(3):

12 At Mount Sinai we have taken a practical approach.

13 Many candidate genes have been described. TGFB1 multifunctional cytokine causes fibrosis SOD2 encodes important anti-oxidant enzyme XRCC3 homologous recombination of DSB XRCC1 single strand break recombination

14 A connection was made between mutations in the ATM gene and prostate radiotherapy side effects in There was an overrepresentation of diabetes in the sequenced population. Cancer J Sc Am (1998) 4:

15 We have used Prostate Brachytherapy as a model for developing a predictive test for side effect incidence.

16 Prostate Brachytherapy as a Model 1.) Very high doses. 2.) Variable patient dosimetry. 3.) Toxicity does happen. 4.) Multiple toxicities can be measured. 5.) Patients live to have late effects. 6.) Toxicities have clinical meaning. 7.) There are few local failures.

17 Pilot study was positive in 37 patients. International J Radiation Oncol Bio Phys (2005) 61:

18 A validation study has been completed in 108 patients. n 108 patients n Age (median) 64 (range 48-79) n Stage T1c 59% T2a-20% T2b-15% n Gleason 5-5% 6-81% 7-12% n PSA % % % n Diabetes, Type II 6/108 6% n Smoking, any 37/108 34% Cesaretti JA, Stock RG, Atencio DP, et al. A genetically determined dose-volume histogram predicts for rectal bleeding among patients treated with prostate brachytherapy. Int J Radiat Oncol Biol Phys Aug 1;68(5): Epub 2007 May 9.

19 Results: Mutational Status Pt. No. Nucleotide Location Codon Mutation Type Amino Acid Change 1,2,3,4,5,6,7,8, 9, G"A 1853 M D"N T"C 54 S Y"Y C"T 604 M P"S A"C 66 S K"K T"C 680 M F"L T"C 707 M S"L A"C 788 M S"R A"G 2614C"T S M L"L P"S C"G 1054 S P"R T"A 415G"A M M D"E A"T T"A 1176C"G IVS7-8insT N/A M S N/A D"E G"G N/A G"A IVS38-8T"C IVS62+8A"C 1853 N/A N/A M N/A N/A D"N N/A N/A

20 Results: Mutational Status Pt. No. Nucleotide Location Codon Mutation Type Amino Acid Change C"T 4388T"G M M P"S F"C C"T 1491 S F"F 24,25, C"T 1526 S P"P G"A 4578C"T 5557G"A IVS38-8T"C 5557H IVS38-8T"C N/A 1853 N/A M S M N/A M N/A D"N P"P D"N N/A D"N N/A A"T 1853 M D"V T"C 1931 S A"A T"C 9200C"G 858 N/A M N/A D"E N/A 33,34,35,36,37, 38,39,40,41,42, 43,44,45 IVS62+8A"C N/A N/A N/A C"T 245 S V"V 47,48 IVS38-8T"C N/A N/A N/A

21 PERCENT WITH GRADE 2 PROCTITIS (5 YR) Defining the Risk of Developing Grade 2 Proctitis Following I-125 Prostate Implants Using a Rectal Dose Volume Histogram Analysis Effect of Rectal Volume Receiving 160 GY pr (<0.8) (> ) (> ) (> ) (>2.3) RECTAL VOLUME (CC) Adapted from Snyder KM, Stock RG, et al, Int. J Rad Oncol Biol Phys 50:335, 2001.

22 Results: Rectal Bleeding Grade 1 and 2 60 % Incidence ATM Alteration Entire Group No ATM Alteration cm 3 exposed to prescription Number of Patients ATM Alteration 4 / 13 4 / 11 6 / 17 2 / 7 No ATM Alteration 1 / 23 1 / 21 3 / 11 3 / 5 Cesaretti JA, Stock RG, Atencio DP, et al. A genetically determined dose-volume histogram predicts for rectal bleeding among patients treated with prostate brachytherapy. Int J Radiat Oncol Biol Phys Aug 1;68(5): Epub 2007 May 9. Fisher s Exact Test p=0.05 p=0.04 p=1 p=0.56

23 In addition to the ATM gene, other promising candidate genes have been tested in prostate brachytherapy patients. n TGF 1 - cytokine associated with deposition of extracellular matrix proteins in irradiated cells. n XRCC1 Important in DNA base excision repair. n SOD2 Involved in cell s response to reactive oxygen species. Anscher MS et al Int J Radiat Oncol Biol Phys 1994;30: De Ruyck K et al Int J Radiat Oncol Biol Phys 2006;65: Andreassen CN et al Radiother Oncol 2005;75: Quarmby S et al Int J Radiat Biol 2003;79:

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25 TGFB Decline in Erectile Function 60 56% p= % 33% TGFβ1 SNP No SNP Population 10 0 TGFβ1 SNP -509TT, No SNP 869CC, 915 9/16 11/45 Population Peters CA, Stock RG, Cesaretti JA, et al. TGFB1 Single Nucleotide Polymorphisms are Associated with Adverse Quality of Life in Prostate Cancer Patients Treated with Radiotherapy. Int J Radiat Oncol Biol Phys Aug 7; [Epub ahead of print]

26 TGFB Rectal Bleeding % p= % 28% TGFβ1 SNP No SNP Population 10 0 TGFβ1-509TT No SNP 6/11 34/130 Population Peters CA, Stock RG, Cesaretti JA, et al. TGFB1 Single Nucleotide Polymorphisms are Associated with Adverse Quality of Life in Prostate Cancer Patients Treated with Radiotherapy. Int J Radiat Oncol Biol Phys Aug 7; [Epub ahead of print]

27 Univariate Analysis for Variables that May Predict for ED Odds Ratio 95% CI P value TGFβ1 SNP Smoking BED 197 Gy Diabetes 0 NA 0.2 CAD HTN Peters CA, Stock RG, Cesaretti JA, et al. TGFB1 Single Nucleotide Polymorphisms are Associated with Adverse Quality of Life in Prostate Cancer Patients Treated with Radiotherapy. Int J Radiat Oncol Biol Phys Aug 7; [Epub ahead of print]

28 Univariate Analysis for Variables that May Predict for Rectal Bleeding TGFβ1 509TT SNP Odds Ratio 95% CI P value Smoking BED 197 Gy v cc Diabetes CAD HTN Peters CA, Stock RG, Cesaretti JA, et al. TGFB1 Single Nucleotide Polymorphisms are Associated with Adverse Quality of Life in Prostate Cancer Patients Treated with Radiotherapy. Int J Radiat Oncol Biol Phys Aug 7; [Epub ahead of print]

29 Association of single nucleotide polymorphisms in SOD2, XRCC1 and XRCC3 with susceptibility for the development of adverse effects resulting from radiotherapy for prostate cancer 2008: 170:49-50 Burri RJ, Cesaretti JA, Stock RG, et al.

30 FIGURE 1

31 FIGURE 2

32 It can t be that simple!

33 It isn t. Combined genetic analysis is more predictive than a single gene model. ATM SEQUENCE VARIANTS AND RISK OF RADIATION-INDUCED SUBCUTANEOUS FIBROSIS AFTER POST-MASTECTOMY RADIOTHERAPY Christian N. Andreassen, M.D., 1 Jens Overgaard, M.D., D.M.Sc., FACR, FRCR 1 Jan Alsner, Ph.D., 1 Marie Overgaard M.D. 2, Carsten Herskind Ph.D., 3 Jamie A. Cesaretti, M.D., 4 David P. Atencio, Ph.D., 4 Sheryl Green, M.D., 4 Silvia C. Formenti, M.D., 7 Richard G. Stock, M.D., 4 Barry S. Rosenstein, Ph.D., 4,5,6,7 IJROBP 2006; 64: ATM codon 1853, XRCC1 codon 399, XRCC3 codon 241, SOD2 codon 16 and TGFB1 codon 10,

34 THE Gene-PARE PROJECT Genetic Predictors of Adverse Radiotherapy Effects 34

35 Genetic Predictors of Adverse Radiotherapy Effects The Gene-PARE Project Funding Agency Treated Cancer Site Country Where Patients Are Accrued Specific Targeted Ethnic Group Period of Study DOD Breast U.S African- American DOD Prostate U.S None NY State Breast & U.S None Dept. of Prostate 2007 Health ACS Prostate U.S African- American VA Prostate U.S None Danish Cancer Society Breast, Head& Neck Denmark None unlimit ed Breast Israel None Breast, Switzerlan None Head & d 2006 Neck COHORT Breast France None Prostate Japan Japanese Screened Genes ATM ATM ATM, TGFB1 XRCC1 XRCC3, SOD2, hhr21 ATM, TGFB1 XRCC1 XRCC3, SOD2, hhr21 ATM, TGFB1 XRCC1 XRCC3, SOD2, hhr21 ATM, TGFB1 XRCC1 XRCC3, SOD2, hhr21 ATM ATM, TGFB1 XRCC1 XRCC3, SOD2, hhr21 ATM ATM, TGFB2, XRCC1, XRCC3, SOD2, hhr21 Adverse Effects Telangiectasia, Fibrosis ED a, UTM b, Proctitis Telangiectasia, Fibrosis ED, UTM, Proctitis ED, UTM, Proctitis ED, UTM, Proctitis Fibrosis, Telangiectasia Telangiectasia, Fibrosis Telangiectasia, Fibrosis Telangiectasia, Fibrosis (Concomitant Letrozole Therapy) ED, UTM, Proctitis

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44 Conclusions n Multiple SNPS can affect normal tissues response to radiation. n GWAS studies and high powered statistical modeling allow the identification of those SNPS n Further studies with greater number of patients will hopefully allow the creation of predicitve models to screen patients for specific radiation side effects

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