1. #1003 Prostate Cancer Update October 5 to October 8 Robert R. Bahnson, MD Louis Levy Professor of Surgery Director, Division of Urology The Ohio State University Medical Center & The James Cancer Hospital and Solove Research Institute Eric A. Klein, MD Head, Section of the Urologic Oncology Cleveland Clinic Foundation

2. Robert R. Bahnson, M.D. Louis Levy Professor of Surgery Director, Division of Urology The Ohio State University Medical Center The James Cancer Hospital and Solove Research Institute, Columbus, Ohio 1

3. Profile Kevin 42 year old white male Father had prostate cancer Healthy otherwise Symptoms - Weakening urination stream - Frequent urination at night - Hesitancy when urinating - Dribbling of urination Kevin 42 year old white male Father had prostate cancer Healthy otherwise Symptoms - Weakening urination stream - Frequent urination at night - Hesitancy when urinating - Dribbling of urination 2

4. Profile Kevin Evaluation - Digital rectal exam - Serum PSA determination Kevin Evaluation - Digital rectal exam - Serum PSA determination 2A

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6. Prostate Cancer Most commonly diagnosed cancer in adult men More than 179,300 men diagnosed in 1999 Estimated 37,000 will die of disease Nearly 20 million males in U.S. forced to make important decisions regarding early detection Controversy has prompted early detection guideline by the American Cancer Society and the American Urologic Assoc. advising a DRE and a serum PSA beginning at age 50 Most commonly diagnosed cancer in adult men More than 179,300 men diagnosed in 1999 Estimated 37,000 will die of disease Nearly 20 million males in U.S. forced to make important decisions regarding early detection Controversy has prompted early detection guideline by the American Cancer Society and the American Urologic Assoc. advising a DRE and a serum PSA beginning at age 50 4

7. Early Screening Opponents point out that randomized trials have not demonstrated a survival benefit in screened patients However, most agree that: - Digital Rectal Exam and Serum PSA have likely played a critical role in the downward prostate cancer stage migration seen in the last 10 years Opponents point out that randomized trials have not demonstrated a survival benefit in screened patients However, most agree that: - Digital Rectal Exam and Serum PSA have likely played a critical role in the downward prostate cancer stage migration seen in the last 10 years 5

8. Guidelines Who are men at high risk? - Those with a family history - All African American men, they should begin an early detection program at age 40 Which men should undergo a biopsy? - Men with a life expectancy exceeding 10 years and a palpable abnormality on digital rectal exam - Men with a PSA greater than 10ng per ml Who are men at high risk? - Those with a family history - All African American men, they should begin an early detection program at age 40 Which men should undergo a biopsy? - Men with a life expectancy exceeding 10 years and a palpable abnormality on digital rectal exam - Men with a PSA greater than 10ng per ml 6

9. Guidelines In screening studies, nearly 3/4 of men will have a normal DRE and a PSA of less than 4 ng/ml Only 15% of this population will have a cancer In screening studies, nearly 3/4 of men will have a normal DRE and a PSA of less than 4 ng/ml Only 15% of this population will have a cancer 7

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12. Recommendations Men with a normal DRE and a PSA greater than 10ng per ml will harbor cancer greater than 50% of the time Therefore, routine biopsy is suggested for men with a 10 year life expectancy if they have an abnormal DRE or a PSA greater than 10ng per ml Men with a normal DRE and a PSA greater than 10ng per ml will harbor cancer greater than 50% of the time Therefore, routine biopsy is suggested for men with a 10 year life expectancy if they have an abnormal DRE or a PSA greater than 10ng per ml 10

13. Prostate-Specific Antigen % Free PSA has emerged as the most clinically useful with the potential to provide: - Improvements in early detection - Staging - And Monitoring of prostate cancer % Free PSA has emerged as the most clinically useful with the potential to provide: - Improvements in early detection - Staging - And Monitoring of prostate cancer 11

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15. Biopsy Procedures Recent evidence suggests change in biopsy technique is needed to increase detection Systemic parasaggital sextant biopsies are widely adopted as standard biopsy procedure New literature suggests optimizing transrectal ultrasound-guided biopsy techniques Recent evidence suggests change in biopsy technique is needed to increase detection Systemic parasaggital sextant biopsies are widely adopted as standard biopsy procedure New literature suggests optimizing transrectal ultrasound-guided biopsy techniques 13

16. Biopsy Procedures Increasing number of biopsies increases likelihood of detecting cancers Risk of finding cancer on repeat biopsy with an initial benign biopsy and an elevated serum PSA is 25% Report by Dr. McCullough shows extended biopsy technique detects more cancers than standard sextant technique Increasing number of biopsies increases likelihood of detecting cancers Risk of finding cancer on repeat biopsy with an initial benign biopsy and an elevated serum PSA is 25% Report by Dr. McCullough shows extended biopsy technique detects more cancers than standard sextant technique 14

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19. Summary Kevin Serum PSA 1.5 ng/ml Prostate slightly enlarged No suspicious findings Follow-Up: - Due to family history, annual prostate exam and testing is recommended Kevin Serum PSA 1.5 ng/ml Prostate slightly enlarged No suspicious findings Follow-Up: - Due to family history, annual prostate exam and testing is recommended 17

20. Eric A Klein, M.D. Head, Section of Urologic Oncology The Cleveland Clinic Foundation Cleveland, Ohio 18

21. Profile Simmons Brothers Brother #1 50 year old man Saw family physician one year ago Prostate was normal upon exam PSA was slightly elevated Prostate biopsy revealed a pre-cancerous condition, Prostatic Intra-epithelial Neoplasia or high-grade PIN Subsequent biopsy confirmed presence of cancer Underwent a radical prostectomy Simmons Brothers Brother #1 50 year old man Saw family physician one year ago Prostate was normal upon exam PSA was slightly elevated Prostate biopsy revealed a pre-cancerous condition, Prostatic Intra-epithelial Neoplasia or high-grade PIN Subsequent biopsy confirmed presence of cancer Underwent a radical prostectomy 19

22. Profile Simmons Brothers Brother #2 In family lounge, met twin brother Recommended he be screened for prostate cancer His biopsy showed high-grade PIN Subsequent biopsy confirmed prostate cancer Underwent a radical prostectomy Genetic testing revealed brothers carried HPC1, which holds a higher risk for development of prostate cancer Simmons Brothers Brother #2 In family lounge, met twin brother Recommended he be screened for prostate cancer His biopsy showed high-grade PIN Subsequent biopsy confirmed prostate cancer Underwent a radical prostectomy Genetic testing revealed brothers carried HPC1, which holds a higher risk for development of prostate cancer 20

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25. Genes And Prostate Cancer Susceptibility Genes - Influence development of cancer Phenotypic Genes - Influence clinical behavior of cancer Susceptibility Genes - Influence development of cancer Phenotypic Genes - Influence clinical behavior of cancer 22

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27. Major Susceptibility Locus For Prostate Cancer on Chromosome 1 Suggested By A Genome-Wide Search Susceptibility locus on long arm of chromosome 1 in certain families Gene area designated as HPC1 On-going intensive efforts to identify gene association with prostate cancer Susceptibility locus on long arm of chromosome 1 in certain families Gene area designated as HPC1 On-going intensive efforts to identify gene association with prostate cancer 24

28. Prostate Cancer Susceptibility Genes HPC1 - 1q24-35 - 9% of cases - Early age of onset - Many affected family members - ? African Americans - ? More advanced stage and grade - Structure and function unknown HPC1 - 1q24-35 - 9% of cases - Early age of onset - Many affected family members - ? African Americans - ? More advanced stage and grade - Structure and function unknown 25

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30. Evidence For A Prostate Cancer Susceptibility Locus On The X Chromosome Three other reports that suggest three additional areas that predispose individuals to prostate cancer HPCX which appeared in Nature in 1998 Epidemiologic observations suggest that men with a brother affected with prostate cancer are more likely to get prostate cancer than those whose father was only affected This suggests linkage with X chromosome Three other reports that suggest three additional areas that predispose individuals to prostate cancer HPCX which appeared in Nature in 1998 Epidemiologic observations suggest that men with a brother affected with prostate cancer are more likely to get prostate cancer than those whose father was only affected This suggests linkage with X chromosome 27

31. Prostate Cancer Susceptibility Genes HPCX - Xq27-28 - 16% of cases - Clinical features undescribed - Structure and function unknown - Not androgen receptor HPCX - Xq27-28 - 16% of cases - Clinical features undescribed - Structure and function unknown - Not androgen receptor 28

32. Predisposing Gene For Early-Onset Prostate Cancer, Localized On Chromosome 1q42.2-43 French Study - Has demonstrated another susceptibility locus on chromosome 1 also on the long arm, but distal at Iq42 French Study - Has demonstrated another susceptibility locus on chromosome 1 also on the long arm, but distal at Iq42 29

33. Pcap Characteristics 1q42.2-43 Associated with early age of onset Phenotype unknown Structure and function unknown 1q42.2-43 Associated with early age of onset Phenotype unknown Structure and function unknown 30

34. Evidence For A Rare Prostate Cancer-Susceptibility Locus At Chromosome 1p36 University of Washington Study - Has identified a 4th susceptibility locus on chromosome 1, on the short arm at 1 p36 University of Washington Study - Has identified a 4th susceptibility locus on chromosome 1, on the short arm at 1 p36 31

35. CAPB Characteristics Chromosome 1p36 Frequent LOH in CNS tumors Not linked to age of onset Linked to FH of CNS tumors Clinical behavior unknown Probably rare Chromosome 1p36 Frequent LOH in CNS tumors Not linked to age of onset Linked to FH of CNS tumors Clinical behavior unknown Probably rare 32

36. Genes And Prostate Cancer Susceptibility Genes - HPC1 - HPCX - Others likely - 4q, 5p, 7p, 13q Phenotypic Genes - Androgen Receptor - “Family history” gene - Androgen metabolism genes Susceptibility Genes - HPC1 - HPCX - Others likely - 4q, 5p, 7p, 13q Phenotypic Genes - Androgen Receptor - “Family history” gene - Androgen metabolism genes 33

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43. #1004 Evaluation & Management of Back Pain October 12 to October 15 Brian Bowyer, MD Associate Professor of Physical Medicine and Rehabilitation Department of Physical Medicine and Rehabilitation The Ohio State University Medical Center Lawrence J. Mervis, M.D. Clinical Associate Professor of Surgery The Ohio State University Medical Center and James Cancer Hospital and Solove Research Institute Columbus, Ohio NEXT WEEK