ASCO GU 2024: Renaming Gleason 3+3 (Grade Group 1): Against

(UroToday.com) The 2024 American Society of Clinical Oncology Genitourinary (ASCO GU) cancers symposium held in San Francisco, CA was host to an “Emerging Evidence in Localized and Recurrent Prostate Cancer” session. Dr. Martin Gleave argued against renaming Gleason 3+3 (Grade Group 1 [GG1]) disease, describing the call to reclassify GG1 disease as ‘flawed’ and ‘misguided’.

He noted that proponents of the nomenclature change claim it is necessary to prevent overtreatment of prostate cancer. While there is a precedent for declassifying bladder (papillary urothelial neoplasm of low malignant potential [PUNLMP]) and thyroid cancers (noninvasive follicular neoplasm with papillary-like nuclear features), these are still completely excised to rule out aggressive histology, while other cancers (e.g., chronic lymphocytic leukemia [CLL] and small renal cell carcinoma [RCC]) are managed by surveillance. But in GG1 prostate cancer, there is already an uncoupling of detection from treatment, and active surveillance is standard of care in many regions. Dr. Gleave argued that we cannot define the biology by social/geographic variables, and it seems that reclassification aims to fix one wrong with another wrong (i.e., fixing the poor active surveillance uptake for GG1 by renaming it), as “this wrong would set in motion unintended consequences that would create more problems than it wants to solve, especially when the uncoupling of detection from treatment is already happening”.

In Dr. Gleave’s opinion, the call for re-classification of GG1 to non-cancer is wrong for the following reasons:

1. Science and Semantics matter
2. Morphology features of Gleason pattern 3 resemble cancer
3. Molecular features of Gleason pattern 3 resemble cancer
4. Natural history of Gleason pattern 3 is not benign
5. Nomenclature change may lead to unintended consequences
6. Simpler solutions exist – guidelines, education, implementation science

Concerning the first point, Dr. Gleave noted that semantics is the branch of linguistics and logic concerned with meaning that allows us to convey and interpret information accurately and is essential when dealing with ambiguity and gradations of certainty. Science helps define ontologies to facilitate analysis, annotation, and understanding. Reclassification sets in motion a trajectory of words, language, and meaning inconsistent with the current scientific understanding of cancer, undermining:

• Intellectual integrity (should promote a belief that you know is not true)
• Integration of future scientific advances that could otherwise improve risk stratification
• Public understanding of the very nature of evidence

What we name something matters – it should reflect a base truth. Neoplasms could be benign or malignant, whereas cancers are malignant. There are some ambiguities where benign tumors can misbehave (neuroma, meningioma) and some malignancies are indolent (CLL, PCa, thyroid, small RCC, in situ breast).

So, what does science tell us here? There are no acceptable alternatives, with labeling GG1 as low malignant potential (LMP) or prostatic acinar intermediate neoplasm being unhelpful, as the implication remains that these are malignant tumors. Additionally, terms that label Gleason pattern 3 simply as a neoplasm are similarly unhelpful, as they define the tumors as being neither benign nor malignant. If GG1 tumors are benign, Dr. Gleave argued that they should be called prostatic acinar adenoma. However, there can be no rational argument that these lesions are inherently benign, despite being low-risk, and importantly as pattern 3 tumour is often intimately associated with higher grade cancer. Given this, it is ‘surprising’ that this option is even considered to be a solution to issues relating to prostate cancer overtreatment in this era of evidence-based medicine that recognizes the value of scientific accuracy. He argued that GG1 has characteristic morphology and molecular features of cancer and a behavior that is not benign - a continuum of aggressiveness with an inflection trajectory between benign and GG1 states.

Tumour grade is one of the most important prognostic indicators of proliferative activity and potential to spread beyond the organ of origin. As such, tumours that are low-grade display less aggressive behaviour characteristics than high-grade cancer. But, by definition, all grades of cancer, including the lower grades, are considered to be malignant with architectural and cytological features of cancer and the ability to invade. In contrast, benign tumours are not able to invade but may show expansion with compression of adjacent structures.

He next argued that Gleason pattern 3 meets all the morphologic criteria seen in higher-grade prostate cancer, which include:

• Absence of basal cells
• Stromal, perineural, extracapsular, and seminal vesicle invasion
  • Clear evidence of harboring invasive characteristics rather than benign accretionary growth
• Metastasis risk is low, but not zero

He noted that tumor grade is not the sole factor to consider in treatment decisions. Tumor volume, T stage, MRI, germline genetics, and genomic testing can all impact the decision to treat. For example, PIRADS 4 and 5 are associated with upgrading - should a patient with a PIRADS 5 GG1 tumor on biopsy be told they do not have cancer? Should a patient with a BRCA2 germline mutations not be treated? Patients should be risk stratified using more than just Gleason score. He argued that, consciously or unconsciously, borderline cases could be upgraded based on these factors.

Another argument against renaming is that Gleason pattern 3 meets the molecular criteria of cancer. Genomic studies have confirmed multifocal, multiclonal heterogeneity within and between patients. Gleason pattern 3 shares similar genomic findings to those seen in higher grade prostate cancer, which include:

• ERG arrangements
• Point mutations, small insertions, deletions, and chromoplexy
• Somatic DNA methylation of CpG islands in GSTP1 
• Androgen receptor cistrome Gleason pattern 3 is similar to that in Gleason pattern 4, which is distinct from that seen in benign tissue

Adjacent Gleason pattern 3 with Gleason pattern 4-5 lesions can originate from the same clones, with Gleason pattern 3 adjacent to Gleason pattern 4-5 lesions sharing a series of mutations and somatic copy number alterations. In an analysis of 82 radical prostatectomy specimens, whole exome sequencing (WES) and transcriptome profiling of laser captured, micro-dissected adjacent Gleason pattern 3 and cribriform Gleason pattern 4 were used to determine the relationship between these entities and established that at least a subset of Gleason pattern 3 and aggressive Gleason pattern 4 tumors have a common origin, supporting a branched evolution model wherein the Gleason pattern 3 and Gleason pattern 4 tumors emerge early from a common precursor and subsequently undergo substantial divergence.¹

Given this clonal and morphologic evolution, Dr. Gleave argued that defining Gleason pattern 3 as non-malignant is not aligned with our current molecular understanding of prostate cancer.

Dr. Gleave next argued that the natural history of GG1 is not benign. He noted that the proponents of a nomenclature change argue that GG1 has never caused a problem – but that is GG1 that is in the ‘pathology bucket’, not on biopsy. But GG1 on biopsy has ≥50% risk of getting upgraded over the subsequent seven to 10 years and has a ≥50% treatment rate, with 10-15% recurrence rates following treatment. These statistics and outcomes are not remotely similar to those in general population (“benign patient”) or in those who have had a negative biopsy (“benign biopsy”).

He also noted that most prostate cancer deaths in patients with GG1 occur 12 – 25 year after diagnosis, with long-term prostate cancer mortality for GG1 patients managed with active surveillance in Sweden at 13%.² Furthermore, in ProtecT, 51% of patients who developed metastases and 46% who died of prostate cancer originally had GG1 disease.³ US SEER data with 20-year follow-up among men who died of prostate cancer, demonstrated that more patients had GG1 disease at diagnosis, versus GG2 or higher (10,020 versus 7,995).⁴

Potential unintended consequences of renaming GG1 include:

• Impact on pathology
  • Biopsy with 6 cores 3+3 and 1 core 3+4 would be signed out as having only a single core of “cancer”, and high-volume 3+3 disease would never trigger treatment
  • If 3+3=6 tumour is benign, then the logical extension is to designate a benign label to the Gleason pattern 3 component of tumour that includes Gleason pattern 4 or 5
  • Gleason scoring would be limited to 4+4=8, 4+5=9, 5+4=9, and 5+5=10, which is inappropriate.
  • Established risk-assessment factors (age, family history, PSA, DRE, imaging, genomics) could not be used to guide the need for treatment (counter-intuitive)
• Impact on active surveillance
  • Compliance is already poor (~25-30%), and would likely be poorer with reclassification⁵
    • Poor compliance correlates with worse outcomes
    • Compliance is lowest in underserved communities and thus racial disparities would potentially increase with re-classification
  • If a pathologist inaccurately grades Gleason pattern 4 as Gleason pattern 3, these men may be compromised by lack of active surveillance
  • Labelling Gleason pattern 3 as non-cancer could push pathologists to upgrade borderline cases, paradoxically leading to more treatment

Dr. Gleave argued that simpler solutions to a nomenclature change exist, which include:

• Increase patient and physician education about the appropriate management of GG1 prostate cancer
• Acknowledge the over-treatment issue and develop evidence-based guidelines to increase the appropriate adoption and the quality of surveillance
• Apply implementation science of methods and procedures to induce urologists to “do the right thing”: Closes the gap between what we know and what we do
• Continue discovery and clinical research to develop new biomarkers:
  • Germline and somatic whole genome sequencing and incorporating artificial intelligence and radiomics

Dr. Gleave concluded his presentation by reiterating his belief that a GG1 nomenclature change is wrong because “two wrongs don’t make a right, because of these six truths or reasoned principles, and the risks of slippery slope and unintended consequences of loosening the tethers of scientific rigor as the goalpost for practicing modern medicine.”


Presented by: Martin Gleave, MD, Distinguished Professor and Head, Department of Urologic Sciences, University of British Columbia, Vancouver, BC

Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2024 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, San Francisco, CA, January 25^th – January 27^th, 2024

References:

1. Bakbak H, Sayar E, Kaur HB, et al. Clonal relationships of adjacent Gleason pattern 3 and Gleason pattern 5 lesions in Gleason Scores 3+5=8 and 5+3=8. Hum Pathol. 2022;130:18-24.
2. Ventimiglia E, Bill-Axelson A, Bratt O, et al. Long-term Outcomes Among Men Undergoing Active Surveillance for Prostate Cancer in Sweden. JAMA Netw Open. 2022;5(9):e2231015.
3. Jamdy FC, Donovan JL, Lane JA, et al. Fifteen-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer. N Engl J Med. 2023;388:1547-58.
4. Clark R, Vesprini D, Narod SA. The Effect of Age on Prostate Cancer Survival. Cancers (Basel). 2022;14(17):4149.
5. Luckenbaugh AN, Auffenberg GB, Hawken SR, et al. Variation in Guideline Concordant Active Surveillance Followup in Diverse Urology Practices. J Urol. 2017;197(3 Pt 1):621-6.