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Which, when and why? Rational use of tissue-based molecular testing in localized prostate cancer

Prostate Cancer and Prostatic Diseases volume 19, pages 1–6 (2016)Cite this article

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Abstract

An increased molecular understanding of localized prostate cancer and the improved ability for molecular testing of pathologic tissue has led to the development of multiple clinical assays. Here we review the relevant molecular biology of localized prostate cancer, currently available tissue-based tests and describe which is best supported for use in various clinical scenarios. Literature regarding testing of human prostate cancer tissue with Ki-67, PTEN (by immunohistochemistry (IHC) or fluroescence in situ hybridization (FISH)), ProMark, Prolaris, OncotypeDX Prostate and Decipher was reviewed to allow for generation of expert opinions. At diagnosis, evaluation of PTEN status, use of ProMark or OncotypeDX Prostate in men with Gleason 6 or 3+4=7 disease may help guide the use of active surveillance. For men with Gleason 7 or above disease considering watchful waiting, Ki-67 and Prolaris add independent prognostic information. For those men who have undergone prostatectomy and have adverse pathology, Decipher testing may aid in the decision to undergo adjuvant radiation. Newly available molecular tests bring opportunities to improve decision making for men with localized prostate cancer. A review of the currently available data suggests clinical scenarios for which each of these tests may have the greatest utility.

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References

  1. Leslie NR, Downes CP . PTEN function: how normal cells control it and tumour cells lose it. Biochem J 2004; 382: 1–11.

    Article  CAS  Google Scholar 

  2. Lotan TL, Gurel B, Sutcliffe S, Esopi D, Liu W, Xu J et al. PTEN protein loss by immunostaining: analytic validation and prognostic indicator for a high risk surgical cohort of prostate cancer patients. Clin Cancer Res 2011; 17: 6563–6573.

    Article  CAS  Google Scholar 

  3. Liu W, Xie CC, Thomas CY, Kim ST, Lindberg J, Egevad L et al. Genetic markers associated with early cancer-specific mortality following prostatectomy. Cancer 2013; 119: 2405–2412.

    Article  CAS  Google Scholar 

  4. Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 2010; 18: 11–22.

    Article  CAS  Google Scholar 

  5. Baca SC, Prandi D, Lawrence MS, Mosquera JM, Romanel A, Drier Y et al. Punctuated evolution of prostate cancer genomes. Cell 2013; 153: 666–677.

    Article  CAS  Google Scholar 

  6. Ding Z, Wu CJ, Chu GC, Xiao Y, Ho D, Zhang J et al. SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. Nature 2011; 470: 269–273.

    Article  CAS  Google Scholar 

  7. Hubbard GK, Mutton LN, Khalili M, McMullin RP, Hicks J, Bianchi-Frias D et al. Abstract 1086: MYC overexpression combined with Pten loss generates genomic instability and rapid metastasis in a new mouse model of lethal prostate andenocarcinoma. Cancer Res 2013; 73: 1066.

    Article  Google Scholar 

  8. Rubin MA, Maher CA, Chinnaiyan AM . Common gene rearrangements in prostate cancer. J Clin Oncol 2011; 29: 3659–3668.

    Article  CAS  Google Scholar 

  9. Haffner MC, Aryee MJ, Toubaji A, Esopi DM, Albadine R, Gurel B et al. Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements. Nat Genet 2010; 42: 668–675.

    Article  CAS  Google Scholar 

  10. Galletti G, Matov A, Beltran H, Fontugne J, Miguel Mosquera J, Cheung C et al. ERG induces taxane resistance in castration-resistant prostate cancer. Nat Commun 2014; 5: 5548.

    Article  CAS  Google Scholar 

  11. Pollack A, DeSilvio M, Khor LY, Li R, Al-Saleem TI, Hammond ME et al. Ki-67 staining is a strong predictor of distant metastasis and mortality for men with prostate cancer treated with radiotherapy plus androgen deprivation: Radiation Therapy Oncology Group Trial 92-02. J Clin Oncol 2004; 22: 2133–2140.

    Article  CAS  Google Scholar 

  12. Khor LY, Bae K, Paulus R, Al-Saleem T, Hammond ME, Grignon DJ et al. MDM2 and Ki-67 predict for distant metastasis and mortality in men treated with radiotherapy and androgen deprivation for prostate cancer: RTOG 92-02. J Clin Oncol 2009; 27: 3177–3184.

    Article  Google Scholar 

  13. Tollefson MK, Karnes RJ, Kwon ED, Lohse CM, Rangel LJ, Mynderse LA et al. Prostate cancer Ki-67 (MIB-1) expression, perineural invasion, and Gleason score as biopsy-based predictors of prostate cancer mortality: the Mayo model. Mayo Clin Proc 2014; 89: 308–318.

    Article  CAS  Google Scholar 

  14. Fisher G, Yang ZH, Kudahetti S, Moller H, Scardino P, Cuzick J et al. Prognostic value of Ki-67 for prostate cancer death in a conservatively managed cohort. Br J Cancer 2013; 108: 271–277.

    Article  CAS  Google Scholar 

  15. Bishoff JT, Freedland SJ, Gerber L, Tennstedt P, Reid J, Welbourn W et al. Prognostic utility of the CCP score generated from biopsy in men treated with prostatectomy. J Urol 2014; 192: 409–414.

    Article  Google Scholar 

  16. Cuzick J, Swanson GP, Fisher G, Brothman AR, Berney DM, Reid JE et al. Prognostic value of an RNA expression signature derived from cell cycle proliferation genes in patients with prostate cancer: a retrospective study. Lancet Oncol 2011; 12: 245–255.

    Article  CAS  Google Scholar 

  17. Cuzick J, Berney DM, Fisher G, Mesher D, Moller H, Reid JE et al. Prognostic value of a cell cycle progression signature for prostate cancer death in a conservatively managed needle biopsy cohort. Br J Cancer 2012; 106: 1095–1099.

    Article  CAS  Google Scholar 

  18. Freedland SJ, Gerber L, Reid J, Welbourn W, Tikishvili E, Park J et al. Prognostic utility of cell cycle progression score in men with prostate cancer after primary external beam radiation therapy. Int J Radiat Oncol Biol Phys 2013; 86: 848–853.

    Article  Google Scholar 

  19. Cuzick J, Yang ZH, Fisher G, Tikishvili E, Stone S, Lanchbury JS et al. Prognostic value of PTEN loss in men with conservatively managed localised prostate cancer. Br J Cancer 2013; 108: 2582–2589.

    Article  CAS  Google Scholar 

  20. Lotan TL, Carvalho FL, Peskoe SB, Hicks JL, Good J, Fedor HL et al. PTEN loss is associated with upgrading of prostate cancer from biopsy to radical prostatectomy. Mod Pathol 2015; 28: 128–137.

    Article  CAS  Google Scholar 

  21. Mithal P, Allott E, Gerber L, Reid J, Welbourn W, Tikishvili E et al. PTEN loss in biopsy tissue predicts poor clinical outcomes in prostate cancer. Int J Urol 2014; 21: 1209–1214.

    Article  CAS  Google Scholar 

  22. Yoshimoto M, Joshua AM, Cunha IW, Coudry RA, Fonseca FP, Ludkovski O et al. Absence of TMPRSS2:ERG fusions and PTEN losses in prostate cancer is associated with a favorable outcome. Mod Pathol 2008; 21: 1451–1460.

    Article  CAS  Google Scholar 

  23. Leinonen KA, Saramaki OR, Furusato B, Kimura T, Takahashi H, Egawa S et al. Loss of PTEN is associated with aggressive behavior in ERG-positive prostate cancer. Cancer Epidemiol Biomarkers Prev 2013; 22: 2333–2344.

    Article  CAS  Google Scholar 

  24. Antonarakis ES, Keizman D, Zhang Z, Gurel B, Lotan TL, Hicks JL et al. An immunohistochemical signature comprising PTEN, MYC, and Ki67 predicts progression in prostate cancer patients receiving adjuvant docetaxel after prostatectomy. Cancer 2012; 118: 6063–6071.

    Article  CAS  Google Scholar 

  25. Shipitsin M, Small C, Choudhury S, Giladi E, Friedlander S, Nardone J et al. Identification of proteomic biomarkers predicting prostate cancer aggressiveness and lethality despite biopsy-sampling error. Br J Cancer 2014; 111: 1201–1212.

    Article  CAS  Google Scholar 

  26. Shipitsin M, Small C, Giladi E, Siddiqui S, Choudhury S, Hussain S et al. Automated quantitative multiplex immunofluorescence in situ imaging identifies phospho-S6 and phospho-PRAS40 as predictive protein biomarkers for prostate cancer lethality. Proteome Sci 2014; 12: 40.

    Article  Google Scholar 

  27. Blume-Jensen P, Berman DM, Rimm DL, Shipitsin M, Putzi M, Nifong TP et al. Development and clinical validation of an in situ biopsy based multi-marker assay for risk stratification in prostate cancer. Clin Cancer Res 2015; 21: 2591–2600.

    Article  CAS  Google Scholar 

  28. Klein EA, Cooperberg MR, Magi-Galluzzi C, Simko JP, Falzarano SM, Maddala T et al. A 17-gene assay to predict prostate cancer aggressiveness in the context of Gleason grade heterogeneity, tumor multifocality, and biopsy undersampling. Eur Urol 2014; 66: 550–560.

    Article  Google Scholar 

  29. Cullen J, Rosner IL, Brand TC, Zhang N, Tsiatis AC, Moncur J et al. A biopsy-based 17-gene genomic prostate score predicts recurrence after radical prostatectomy and adverse surgical pathology in a racially diverse population of men with clinically low- and intermediate-risk prostate cancer. Eur Urol 2014; 29 November 2014; S0302-2838(14)01213-5; (e-pub ahead of print).

  30. Erho N, Crisan A, Vergara IA, Mitra AP, Ghadessi M, Buerki C et al. Discovery and validation of a prostate cancer genomic classifier that predicts early metastasis following radical prostatectomy. PLoS One 2013; 8: e66855.

    Article  CAS  Google Scholar 

  31. Karnes RJ, Bergstralh EJ, Davicioni E, Ghadessi M, Buerki C, Mitra AP et al. Validation of a genomic classifier that predicts metastasis following radical prostatectomy in an at risk patient population. J Urol 2013; 190: 2047–2053.

    Article  CAS  Google Scholar 

  32. Klein EA, Yousefi K, Haddad Z, Choeurng V, Buerki C, Stephenson AJ et al. A genomic classifier improves prediction of metastatic disease within 5 years after surgery in node-negative high-risk prostate cancer patients managed by radical prostatectomy without adjuvant therapy. Eur Urol 2014; 67: 778–786.

    Article  Google Scholar 

  33. Ross AE, Johnson MH, Yousefi K, Davicioni E, Fedor H, Glavaris S et al. Tissue-based genomics to augment post-prostatectomy risk stratification in a natural history cohort. JCO 2015; 33(Suppl): 5059.

    Article  Google Scholar 

  34. Den RB, Feng FY, Showalter TN, Mishra MV, Trabulsi EJ, Lallas CD et al. Genomic prostate cancer classifier predicts biochemical failure and metastases in patients after postoperative radiation therapy. Int J Radiat Oncol Biol Phys 2014; 89: 1038–1046.

    Article  Google Scholar 

  35. Den RB, Yousefi K, Trabulsi EJ, Abdollah F, Choeurng V, Feng FY et al. Genomic classifier identifies men with adverse pathology after radical prostatectomy who benefit from adjuvant radiation therapy. J Clin Oncol 2015; 33: 944–951.

    Article  Google Scholar 

  36. Ross AE, Feng FY, Ghadessi M, Erho N, Crisan A, Buerki C et al. A genomic classifier predicting metastatic disease progression in men with biochemical recurrence after prostatectomy. Prostate Cancer Prostatic Dis 2014; 17: 64–69.

    Article  CAS  Google Scholar 

  37. Bill-Axelson A, Holmberg L, Garmo H, Rider JR, Taari K, Busch C et al. Radical prostatectomy or watchful waiting in early prostate cancer. N Engl J Med 2014; 370: 932–942.

    Article  CAS  Google Scholar 

  38. Wilt TJ, Brawer MK, Jones KM, Barry MJ, Aronson WJ, Fox S et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 2012; 367: 203–213.

    Article  CAS  Google Scholar 

  39. Klotz L, Vesprini D, Sethukavalan P, Jethava V, Zhang L, Jain S et al. Long-term follow-up of a large active surveillance cohort of patients with prostate cancer. J Clin Oncol 2015; 33: 272–277.

    Article  Google Scholar 

  40. Alam R, Carter HB, Landis P, Epstein JI, Mamawala M . Conditional probability of reclassification within an active surveillance program for prostate cancer. J Urol 2015; 193: 1950–1955.

    Article  Google Scholar 

  41. Tosoian JJ, Trock BJ, Landis P, Feng Z, Epstein JI, Partin AW et al. Active surveillance program for prostate cancer: an update of the Johns Hopkins experience. J Clin Oncol 2011; 29: 2185–2190.

    Article  Google Scholar 

  42. Davis JW . Novel commercially available genomic tests for prostate cancer: a roadmap to understanding their clinical impact. BJU Int 2014; 114: 320–322.

    PubMed  Google Scholar 

  43. Polley MY, Leung SC, McShane LM, Gao D, Hugh JC, Mastropasqua MG et al. An international Ki67 reproducibility study. J Natl Cancer Inst 2013; 105: 1897–1906.

    Article  Google Scholar 

  44. D'Amico AV . Personalizing the duration of androgen-deprivation therapy use in the management of intermediate-risk prostate cancer. J Clin Oncol 2015; 33: 301–303.

    Article  Google Scholar 

  45. Thompson IM, Valicenti RK, Albertsen P, Davis BJ, Goldenberg SL, Hahn C et al. Adjuvant and salvage radiotherapy after prostatectomy: AUA/ASTRO Guideline. J Urol 2013; 190: 441–449.

    Article  Google Scholar 

  46. Freedland SJ, Rumble RB, Finelli A, Chen RC, Slovin S, Stein MN et al. Adjuvant and salvage radiotherapy after prostatectomy: American Society of Clinical Oncology clinical practice guideline endorsement. J Clin Oncol 2014; 32: 3892–3898.

    Article  Google Scholar 

  47. Bolla M, van Poppel H, Tombal B, Vekemans K, Da Pozzo L, de Reijke TM et al. Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911). Lancet 2012; 380: 2018–2027.

    Article  Google Scholar 

  48. Thompson IM Jr., Tangen CM, Paradelo J, Lucia MS, Miller G, Troyer D et al. Adjuvant radiotherapy for pathologically advanced prostate cancer: a randomized clinical trial. JAMA 2006; 296: 2329–2335.

    Article  CAS  Google Scholar 

  49. Pearse M, Fraser-Browne C, Davis ID, Duchesne GM, Fisher R, Frydenberg M et al. A Phase III trial to investigate the timing of radiotherapy for prostate cancer with high-risk features: background and rationale of the Radiotherapy–Adjuvant Versus Early Salvage (RAVES) trial. BJU Int 2014; 113: 7–12.

    Article  Google Scholar 

  50. Shore N, Concepcion R, Saltzstein D, Lucia MS, van Breda A, Welbourn W et al. Clinical utility of a biopsy-based cell cycle gene expression assay in localized prostate cancer. Curr Med Res Opin 2014; 30: 547–553.

    Article  Google Scholar 

  51. Crawford ED, Scholz MC, Kar AJ, Fegan JE, Haregewoin A, Kaldate RR et al. Cell cycle progression score and treatment decisions in prostate cancer: results from an ongoing registry. Curr Med Res Opin 2014; 30: 1025–1031.

    Article  Google Scholar 

  52. Apolo AB, Riches J, Schoder H, Akin O, Trout A, Milowsky MI et al. Clinical value of fluorine-18 2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography in bladder cancer. J Clin Oncol 2010; 28: 3973–3978.

    Article  Google Scholar 

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Acknowledgements

AER is funded by the Johns Hopkins Clinician Scientist Award, Patrick Walsh Research Fund and the DOD Prostate Cancer Physician Research Training Award.

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Authors and Affiliations

  1. Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    A E Ross

  2. Department of Oncology, James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    A E Ross

  3. Department of Pathology, James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    A E Ross

  4. Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    A V D'Amico

  5. Division of Urology, Department of Surgery, Cedars-Siani Medical Center, Los Angeles, CA, USA

    S J Freedland

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Correspondence to A E Ross.

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Competing interests

AER has received compensation for consultation from GenomeDx Biosciences (manufacturers of Decipher). SJF has performed collaborative research with Myriad (manufacturers of Prolaris) and GenomeDx Biosciences. AVD declares no conflict of interest.

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Ross, A., D'Amico, A. & Freedland, S. Which, when and why? Rational use of tissue-based molecular testing in localized prostate cancer. Prostate Cancer Prostatic Dis 19, 1–6 (2016). https://doi.org/10.1038/pcan.2015.31

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