Minor variations in biopsy-assigned Gleason scores offer robust stratification of survival outcomes for men treated with external beam radiation therapy for prostate cancer, "Beyond the Abstract," by Chad G. Rusthoven, et al.

BERKELEY, CA (UroToday.com) - In 1966, Donald Gleason described a novel system for the grading of prostate cancer based on the architectural pattern of tumor cells, today known as the Gleason score.[1] This system was modified during the 1970s to include a spectrum morphologic patterns (scored 1-5) and was innovative in the assignment of an overall Gleason sum (scored 2-10) totaling the primary and secondary patterns of disease. In the nearly 5 decades since Gleason’s initial publication, the landscape of diagnosis and management for localized prostate cancer has changed dramatically, including the introduction of PSA testing, transrectal ultrasound-guided needle biopsy, axial CT and MRI imaging, radical retropubic prostatectomy techniques, dose-escalated image guided radiation, and the much expanded use of androgen deprivation therapy (ADT). Remarkably, the Gleason grading system remains ubiquitous and essential to the prediction of surgical pathology, disease progression, and prognosis.

“Chaos was the law of nature; order was the dream of man.”
- Henry Adams, The Education of Henry Adams, 1907

Historically, Gleason scores of ≤ 6, 7, and 8-10 have been analyzed as homogenous risk groups, corresponding to low-, intermediate-, and high-grade histology, respectively. Stratified survival outcomes for this three-tiered system are well validated, but there is mounting evidence to suggest that these categories may overlook substantial intra-group prognostic information. Over the past decade, numerous studies have reported stratified outcomes within these broad groupings based on primary-secondary patterns (e.g., 3+4 vs 4+3) and overall Gleason scores (e.g., 8 vs 9 vs 10). The vast majority of these studies have reported on biochemical control as a primary endpoint. However, biochemical progression represents an early event in the natural history of prostate cancer and is not an accepted surrogate for prostate cancer-specific mortality. This disconjugation between biochemical progression and mortality is also likely to increase in a landscape of rapidly improving systemic therapy options for recurrent and metastatic disease. The few analyses which have reported on survival outcomes for refined Gleason stratifications have also been limited by a focus on single stratification levels (e.g., 3+4 vs 4+3) in isolation, relatively small patient numbers, and the inability to demonstrate persistent prognostic stratifications on both univariate and multivariate analyses adjusting for important prognostic factors such as PSA and T stage.[2,3]

In this manuscript titled, “Gleason stratifications prognostic for survival in men receiving definitive external beam radiation therapy for localized prostate cancer,” the survival outcomes for > 26 000 patients in the United States diagnosed from 2004–2006 with Gleason 6-10 prostate cancer were comprehensively evaluated in an effort to identify Gleason stratifications prognostic for survival at the population level.[4] Here, biopsy-assigned Gleason scores of 3+3, 3+4, 4+3, 4+4, 8 with pattern 5 (ie, 3+5 or 5+3), 9, and 10 represented sequential prognostic factors for survival, with each individual level corresponding to a statistically significant increase in the risk of prostate cancer-specific mortality.

To echo simply that the Gleason score is an important, if not the most important, prognostic factor for localized prostate cancer would, admittedly, add little to a contemporary discourse. However, there are a number of features unique to this observational study that add granularity to the discussion of Gleason scores in the modern era. First, a key strength of the present study is the primary analysis of survival outcomes, which avoids the confounders inherent to surrogate endpoints. Second, Gleason stratifications from 6-10 were evaluated comprehensively and sequentially, rather than evaluating single level increases in isolation. As a result, the prognostic importance of each score, relative to all other scores, may be inferred from these outcomes. Third, the observation of significant survival differences on univariate analyses persisted (with the exception of a trend toward improved survival for Gleason 8 with pattern 5 vs 9) when accounting for PSA, T stage, and age, as well as socio-economic and health care access surrogates.

The observed 7.5-year prostate cancer-specific survival rates were 99%, 97%, 95%, 91%, 86%, 81%, and 78% for Gleason scores of Gleason scores of 3+3, 3+4, 4+3, 4+4, 8 with pattern 5, 9, and 10, respectively. In a critical appraisal of our reported data, we submit that a number of these absolute survival differences are modest. Moreover, the identification of statistical significance does not necessarily correspond with clinical significance, and the demonstration of the former is certainly aided by the large patient numbers in this analysis. And, given the indications for increasing use and duration of ADT with higher Gleason scores, it is likely that the absolute mortality risks between these stratifications were, in fact, underestimated. Nevertheless, statistical significance fundamentally corresponds to confidence intervals and conventional analytic thresholds which, when crossed, allow for the assertion that observed stratifications are real, rather than a product of chance. Overall, this analysis relies on large patient numbers to confidently state that small variations in the presence and extent of higher grade Gleason patterns on prostate biopsy are associated with modest but real differences in prostate cancer-specific mortality for men receiving radiation therapy. The subjective clinical significance of this observation will vary based on the intended applications, such as patient counseling, risk stratification, and data analysis.

In this study, one particularly illustrative analysis evaluated the relative prognostic significance of single tier increases in the 7 biopsy-assigned Gleason stratifications listed above, compared to traditional PSA risk stratifications (< 10, 10–19.9, and ≥ 20 ng/ml; scored 1–3) and T stages (scored 1-4). In this model, single level increases among the 7 identified Gleason stratifications were globally more important than traditional PSA risk tiers and T stage. This observation is remarkable given the increased number of analyzed Gleason tiers, which would be expected to dilute the hazard differentials offered by single level increases. In other words, seemingly minor variations in biopsy-assigned Gleason scores (e.g., 3+4 vs 4+3, or 9 vs 10) carried greater prognostic significance than conventional PSA stratifications (e.g., 10-19.9 vs ≥ 20 ng/ml) and broad T stage assignments (e.g., T2 vs T3) for men treated with radiation therapy during this contemporary 3-year interval.

In some ways it is difficult to believe that now, nearly 50 years from its initial description, a histologic grading system dependent on light microscopy has endured as arguably the most robust prognostic factor for localized prostate cancer. It also may be tempting to assume that genomic profiling may soon replace phenotypic Gleason assignments which, despite rigorous criteria, are inherently dependent on subjective interpretation. Multi-gene expression profiling assays, such as the Oncotype DX® and MammaPrint® panels, have notably demonstrated prognostic and predictive value in breast cancer and are increasingly being incorporated into clinical management decisions.[5] However, these assays do not replace, but rather add to, the prognostication offered by validated traditional clinical factors in breast cancer, such as TNM staging and receptor status. Similarly, the NCCN guidelines now recognize early advancements in RNA expression panels for prostate cancer, including the Cell Cycle Progression (CCP) score and Genomic Prostate Score (GPS).[6] Overall, early studies of these panels have demonstrated enhancement of traditional stratification models (including Gleason, PSA, and T stage), notably as new independent prognostic factors, without consistent correlation with other factors or significant prognostic interactions.

There remains much to learn, given the inherent chaos of cancer biology that can drive tumor behavior in a sometimes unpredictable fashion,[7] and the present study is certainly not the final word on establishing order. Nevertheless, it is comforting to know that even as we transition into the molecular age of oncology, the basic architectural patterns of prostate cancer, famously described in the corridors of the Minneapolis VA Medical Center in the 1960s, are likely to maintain a fundamental role in risk stratification and treatment selection for men with localized prostate cancer.

References:

  1. Gleason DF. Classification of prostatic carcinomas. Cancer Chemotherapy Reports Part 1 1966;50:125-128.
  2. Stark JR, Perner S, Stampfer MJ, et al. Gleason score and lethal prostate cancer: Does 3 + 4 = 4 + 3? Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 2009;27:3459-3464.
  3. Wright JL, Salinas CA, Lin DW, et al. Prostate cancer specific mortality and gleason 7 disease differences in prostate cancer outcomes between cases with gleason 4 + 3 and gleason 3 + 4 tumors in a population based cohort. Journal of Urology 2009;182:2702-2707.
  4. Rusthoven CG, Waxweiler TV, DeWitt PE, et al. Gleason stratifications prognostic for survival in men receiving definitive external beam radiation therapy for localized prostate cancer. Urologic Oncology 2014.
  5. The National Comprehensive Cancer Network (NCCN) Clincical Practice Guidelines in Oncology: Breast cancer, v 3.2014. http://www.Nccn.Org/professionals/physician_gls/pdf/prostate.Pdf accessed November 22, 2014.
  6. The National Comprehensive Cancer Network (NCCN)  Clincical Practice Guidelines in Oncology: Prostate cancer, v 1.2015. http://www.Nccn.Org/professionals/physician_gls/pdf/prostate.Pdf accessed November 22, 2014.
  7. Coffey DS. Self-organization, complexity and chaos: The new biology for medicine. Nature Medicine 1998;4:882-885.

Written by:
Chad G. Rusthoven, Timothy V. Waxweiler, and Brian D. Kavanagh as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

University of Colorado School of Medicine, Department of Radiation Oncology, Aurora, CO USA

Gleason stratifications prognostic for survival in men receiving definitive external beam radiation therapy for localized prostate cancer - Abstract

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