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Clinical and molecular rationale to retain the cancer descriptor for Gleason score 6 disease

Nature Reviews Urology volume 14, pages 59–64 (2017)Cite this article

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Abstract

Treatment choices for men with indolent prostate cancer include active surveillance or definitive local therapy. Overtreatment of these patients is an important current problem. Treatment decisions are often made jointly by the clinician and the patient, partly based on the tumour's Gleason score. To reduce the burden of overtreatment, the clinical significance of Gleason score 3 + 3 = 6 prostate cancer has been questioned and some have advocated that Gleason pattern 3 should be stripped of its cancer status. However, removing the cancer descriptor would have far-reaching clinical consequences that might result in poor patient outcomes, as the evidence of a lack of malignancy is inconclusive in several areas. For example, molecular data suggest that the genomic instability underlying tumour progression precedes histologically visible changes and the absolute risk of metastasis or mortality from Gleason score 6 prostate cancer is not zero. Extreme caution is required when weighing a decision to reclassify Gleason pattern 3 disease as a non-cancer.

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Figure 1: The malignant potential of Gleason pattern 3 prostate cancer.

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References

  1. Magi-Galluzzi, C. et al. Gene expression in normal-appearing tissue adjacent to prostate cancers are predictive of clinical outcome: evidence for a biologically meaningful field effect. Oncotarget 7, 33855–33865 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Gnanapragasam, V. J. et al. The Prostate Health Index adds predictive value to multi-parametric MRI in detecting significant prostate cancers in a repeat biopsy population. Sci. Rep. 6, 35364 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Haffner, M. C., De Marzo, A. M., Yegnasubramanian, S., Epstein, J. I. & Carter, H. B. Diagnostic challenges of clonal heterogeneity in prostate cancer. J. Clin. Oncol. 33, e38–e40 (2015).

    Article  PubMed  Google Scholar 

  4. Tosoian, J. J. et al. Intermediate and longer-term outcomes from a prospective active-surveillance program for favorable-risk prostate cancer. J. Clin. Oncol. 33, 3379–3385 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Bell, K. J., Del Mar, C., Wright, G., Dickinson, J. & Glasziou, P. Prevalence of incidental prostate cancer: a systematic review of autopsy studies. Int. J. Cancer 137, 1749–1757 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Miah, S., Ahmed, H. U., Freeman, A. & Emberton, M. Does true Gleason pattern 3 merit its cancer descriptor? Nat. Rev. Urol. 13, 541–548 (2016).

    Article  PubMed  Google Scholar 

  7. Thompson, I. M. et al. Assessing prostate cancer risk: results from the Prostate Cancer Prevention Trial. J. Natl Cancer Inst. 98, 529–534 (2006).

    Article  PubMed  Google Scholar 

  8. Weiner, A. B., Etzioni, R. & Eggener, S. E. Ongoing Gleason grade migration in localized prostate cancer and implications for use of active surveillance. Eur. Urol. 66, 611–612 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Danneman, D., Drevin, L., Robinson, D., Stattin, P. & Egevad, L. Gleason inflation 1998–2011: a registry study of 97 168 men. BJU Int. 115, 248–255 (2015).

    Article  CAS  PubMed  Google Scholar 

  10. Albertsen, P. C. et al. Prostate cancer and the Will Rogers phenomenon. J. Natl Cancer Inst. 97, 1248–1253 (2005).

    Article  PubMed  Google Scholar 

  11. Epstein, J. I., Allsbrook, W. C., Amin, M. B., Egevad, L. L. & ISUP Grading Committee. The 2005 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma. Am. J. Surg. Pathol. 29, 1228–1242 (2005).

    Article  PubMed  Google Scholar 

  12. Epstein, J. I. et al. A contemporary prostate cancer grading system: a validated alternative to the Gleason score. Eur. Urol. 69, 428–435 (2016).

    Article  PubMed  Google Scholar 

  13. Epstein, J. I. et al. The 2014 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma: definition of grading patterns and proposal for a new grading system. Am. J. Surg. Pathol. 40, 244–252 (2016).

    PubMed  Google Scholar 

  14. Pierorazio, P. M., Walsh, P. C., Partin, A. W. & Epstein, J. I. Prognostic Gleason grade grouping: data based on the modified Gleason scoring system. BJU Int. 111, 753–760 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Berman, D. M. & Epstein, J. I. When is prostate cancer really cancer? Urol. Clin. North Am. 41, 339–346 (2014).

    Article  PubMed  Google Scholar 

  16. Carter, H. B. et al. Gleason score 6 adenocarcinoma: should it be labeled as cancer? J. Clin. Oncol. 30, 4294–4296 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Sonn, G. A. et al. Initial experience with electronic tracking of specific tumor sites in men undergoing active surveillance of prostate cancer. Urol. Oncol. 32, 952–957 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Palapattu, G. et al. Molecular progression of Gleason 6 prostate cancer: tracking of specific clones by image-guided biopsy [abstract PD08-07]. J. Urol. 195 (Suppl.), e230–e231 (2016).

    Google Scholar 

  19. Eggener, S. E. et al. Predicting 15-year prostate cancer specific mortality after radical prostatectomy. J. Urol. 185, 869–875 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Schiffmann, J. et al. Tumor volume in insignificant prostate cancer: increasing threshold gains increasing risk. Prostate 75, 45–49 (2015).

    Article  CAS  PubMed  Google Scholar 

  21. Albertsen, P. C., Hanley, J. A. & Fine, J. 20-year outcomes following conservative management of clinically localized prostate cancer. JAMA 293, 2095–2101 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Klotz, L. et al. Long-term follow-up of a large active surveillance cohort of patients with prostate cancer. J. Clin. Oncol. 33, 272–277 (2015).

    Article  PubMed  Google Scholar 

  23. Hamdy, F. C. et al. 10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. N. Engl. J. Med. 375, 1415–1424 (2016).

    Article  PubMed  Google Scholar 

  24. Bill-Axelson, A. et al. Radical prostatectomy or watchful waiting in early prostate cancer. N. Engl. J. Med. 370, 932–942 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Klein, E. A. 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. 66, 550–560 (2014).

    Article  PubMed  Google Scholar 

  26. Ross, H. M. et al. Do adenocarcinomas of the prostate with Gleason score (GS) ≤6 have the potential to metastasize to lymph nodes? Am. J. Surg. Pathol. 36, 1346–1352 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Haffner, M. C. et al. Tracking the clonal origin of lethal prostate cancer. J. Clin. Invest. 123, 4918–4922 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nakabayashi, M. et al. Clinical predictors of survival in men with castration-resistant prostate cancer: evidence that Gleason score 6 cancer can evolve to lethal disease. Cancer 119, 2990–2998 (2013).

    Article  PubMed  Google Scholar 

  29. Klein, E. A. et al. Molecular analysis of low grade prostate cancer utilizing a genomic classifier of metastatic potential. J. Urol. http://dx.doi.org/10.1016/j.juro.2016.08.091 (2016).

  30. Karnes, R. J. et al. Validation of a genomic classifier that predicts metastasis following radical prostatectomy in an at risk patient population. J. Urol. 190, 2047–2053 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Erho, N. et al. Discovery and validation of a prostate cancer genomic classifier that predicts early metastasis following radical prostatectomy. PLoS ONE 8, e66855 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lalonde, E. et al. Tumour genomic and microenvironmental heterogeneity for integrated prediction of 5-year biochemical recurrence of prostate cancer: a retrospective cohort study. Lancet Oncol. 15, 1521–1532 (2014).

    Article  PubMed  Google Scholar 

  33. Polson, E. S. et al. Monoallelic expression of TMPRSS2/ERG in prostate cancer stem cells. Nat. Commun. 4, 1623 (2013).

    Article  PubMed  CAS  Google Scholar 

  34. Lotan, T. L. et al. PTEN loss is associated with upgrading of prostate cancer from biopsy to radical prostatectomy. Mod. Pathol. 28, 128–137 (2015).

    Article  CAS  PubMed  Google Scholar 

  35. Lotan, T. L. 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. 17, 6563–6573 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hubbard, G. K. et al. Combined MYC activation and Pten loss are sufficient to create genomic instability and lethal metastatic prostate cancer. Cancer Res. 76, 283–292 (2016).

    Article  CAS  PubMed  Google Scholar 

  37. Gundem, G. et al. The evolutionary history of lethal metastatic prostate cancer. Nature 520, 353–357 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Cooper, C. S. et al. Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue. Nat. Genet. 47, 367–372 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Trock, B. J. et al. PTEN loss and chromosome 8 alterations in Gleason grade 3 prostate cancer cores predicts the presence of un-sampled grade 4 tumor: implications for active surveillance. Mod. Pathol. 29, 764–771 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Rubin, M. A., Girelli, G. & Demichelis, F. Genomic correlates to the newly proposed grading prognostic groups for prostate cancer. Eur. Urol. 69, 557–560 (2016).

    Article  PubMed  Google Scholar 

  41. Tomlins, S. A. et al. Characterization of 1577 primary prostate cancers reveals novel biological and clinicopathologic insights into molecular subtypes. Eur. Urol. 68, 555–567 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Reichard, C. A., Stephenson, A. J. & Klein, E. A. Applying precision medicine to the active surveillance of prostate cancer. Cancer 121, 3403–3411 (2015).

    Article  PubMed  Google Scholar 

  43. Reichard, C. A., Stephenson, A. J. & Klein, E. A. Molecular markers in urologic oncology: prostate cancer. Curr. Opin. Urol. 26, 225–230 (2016).

    Article  PubMed  Google Scholar 

  44. Klein, E. A. 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. 67, 778–786 (2015).

    Article  PubMed  Google Scholar 

  45. Klein, E. A. et al. Decipher genomic classifier measured on prostate biopsy predicts metastasis risk. Urology 90, 148–152 (2016).

    Article  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Chad A. Reichard and Eric A. Klein are at the Cleveland Clinic, Glickman Urological & Kidney Institute, 9500 Euclid Avenue, Q10-1, Cleveland, Ohio 44195, USA.,

    Chad A. Reichard & Eric A. Klein

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Contributions

C.A.R. researched data for the article and wrote the manuscript. Both authors discussed the article's content and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Eric A. Klein.

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Competing interests

E.A.K. has served as consultant for GenomeDx, Genomic Health and Metamark, has previously received grant support from GenomeDx, Genomic Health and Metamark, and has received payment for lectures from Genomic Health. C.A.R. declares no competing interest.

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Reichard, C., Klein, E. Clinical and molecular rationale to retain the cancer descriptor for Gleason score 6 disease. Nat Rev Urol 14, 59–64 (2017). https://doi.org/10.1038/nrurol.2016.240

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