Renaming Gleason 6 Prostate Cancer

At the Society of Urologic Oncology meeting held in conjunction with the 2023 American Urological Association annual meeting in Chicago, the Prostate Cancer session featured a debate between Dr. Catalona and Dr. Cooperberg regarding the notion of renaming of Gleason 6 (Grade Group 1) prostate cancer to remove the cancer terminology.

Dr. Catalona presented first, making the argument that we, as a field, should not renaming Grade Group 1 prostate cancer terming such an idea “misguided”. He began by noting that proponents of this ideas cite the precedent from other entities with low malignant potential such as low-grade bladder cancer (papillary urothelial neoplasm of low malignant potential; PUNLMP) and thyroid cancer (non-invasive follicular neoplasm with papillary-like nuclear features). However, he argued that these labels are applied after the lesion has been excised, not just biopsied.

Further, Dr. Catalona noted that there is data from the ProtecT trial showing comparable survival outcomes for patients with prostate cancer managed with active treatment, or active monitoring. Additionally, he noted that advocates of renaming low-grade prostate cancer cited the potential to decrease overtreatment as a rationale. However, he suggested that increasing uptake of active surveillance, in the neighborhood of 60 to 80% depending on the population examined, in the current context justifies retaining the cancer label.

He further noted that proponents of relabeling have suggested that diagnosis of Grade Group 1 disease will decrease with increasing utilization of MRI and targeted biopsy. He argued, however, that at an individual patient level there would remain a large group of patients with this diagnosis, at the population-level.

He further suggested that renaming Grade Group 1 disease would “deceive” patients, citing the fact that prostate cancers are often multi-focal with differing disease characteristics in different foci. Further, he noted that there are limitations to systematic biopsy which may result in underdiagnosis. Further, he noted that Grade Group 1 disease may be genetically heterogeneous.

He further sought to counter claims that Grade Group 1 disease never metastasizes by arguing that these data are derived from patients who underwent prostatectomy, a circumstance in which their disease may have been cured by the treatment. Additionally, he discussed histologic morphology data noting that these tumors may exhibit some degree of local invasiveness, lack a basal cell layer, and may have invasion of perineural tissues or rarely extracapsular extension. He further suggested that molecular data support the definition of Grade Group 1 disease as a cancer by noting that there may be substantial heterogeneity and these tumors may exhibit genetic changes also seen in higher grade disease. Coming back to a discussion of the implications of increasing MRI utilization, he noted that MRI invisible lesions may be biologically relevant.

He then moved to a discussion of the clinical behavior of patients with Grade Group 1 disease, noting a significant proportion of these will experience upgrading or reclassification while on active surveillance. Supporting the clinical relevance of this, he noted that a majority of patients who developed metastatic disease on ProtecT were initially diagnosed with Gleason 6 disease.

He further sought to highlight the limitations of the available data, noting that oncologic outcomes for patients with Grade Group 1 disease are anticipated to occur 12 to 25 years after diagnosis. Studies with follow-up of this duration have suggested that up to 13% of patients with Grade Group 1 disease managed with active surveillance may eventually die of prostate cancer.

Premised on these arguments, he asserted that remaining Grade Group 1 disease as a “non-cancer” would result in decreased utilization or adherence to active surveillance resulting in worse clinical outcomes. He then quoted the authors of the recent ProtecT manuscript who emphasized the need for improved risk-stratification tools in this disease space, emphasizing the potential for germline genomic testing, somatic tumor testing, radiomics, and artificial intelligence based pathology interpretation.

He closed by suggesting that the way forward is to acknowledge ongoing issues with overtreatment of low-risk prostate cancer while retaining the current nomenclature.

Following Dr. Catalona’s presentation, Dr. Cooperberg argued that we should rename Grade Group 1 prostate cancer, removing the cancer label. Dr. Cooperberg emphasized that there may be substantial public health benefits derived from removing the cancer label from patients with Grade Group 1 disease. To this end, he highlighted that our terminology should be patient-centered: patients focus lesion potential similarities or differences on a histologic level but focus on considerations regarding treatment burden and prognosis when hearing the word “cancer”.

He first noted that the diagnosis of Grade Group 1 disease is essentially a feature of the normal aging process: 50% of black men will harbor autopsy detectable prostate cancer by age 70 and a similar proportion of white men will have the disease by age 80.

Further, based on studies of thousands of patients, he emphasized that the renowned pathology Jonathan Epstein has noted that Gleason score 6 disease “does not appear to metastasize to lymph nodes”. While he acknowledged that Grade Group 1 does harbor some genomic changes associated with malignancy, he emphasized that histologically normal tissue may also harbor these changes.

Thus, in totality, he emphasized that Gleason 6 disease does not met the hallmarks of malignancy: self-sufficiency in growth signals, insensitivity to growth inhibition signaling, resistance to apoptosis signals, unlimited replicative potential, sustained angiogenesis, and tissue invasion and metastasis. Thus, citing the common aphorism, he noted that despite histologic appearances similar to cancer, Grade Group 1 disease is more akin to a decoy, than a duck, having the appearance but not the behavior. He further emphasized that there is a spectrum of biology from truly “normal” tissue through to aggressive disease. The current definition of cancer represents an arbitrary distinction between pre-tumorous lesions such as ASAP/PIN and Grade Group 1 disease while a line between Grade Group 1 and 2 would be no less arbitrary.

Additionally, he emphasized that, through the use of biomarkers and imaging, we (as a field) are increasingly seeking to avoid the diagnosis of Grade Group 1 disease. These efforts, along with grade migration, are increasingly proving efficacious with decreasing rates of diagnosis of Grade Group 1 disease. Running in parallel to this, he noted that there has been increasing use of active surveillance for low-risk disease. However, he emphasized that there remains substantial variation both at the practice and practitioner level in terms of adoption.

Moving from the individual patient perspective to consider public health implications more broadly, he emphasized that public health recommendations (ie, USPSTF) against prostate cancer screening have coming from concerns regarding overdiagnosis and overtreatment. Increasing utilization of surveillance was explicitly cited as a rationale for the change from a Grade D to C recommendation in 2017. Thus, the greatest population-level effect may come from changes we can make to encourage more primary care practitioners to embrace early baseline PSA testing. Key in doing this is to reduce the overdiagnosis of clinically indolent disease.

He closed by noting that Gleason Grade Group 1 disease is an exceptionally common feature of male aging which is essentially an incidental effect of our efforts to screen for more aggressive disease. Further, renamed Grade Group 1 disease would still require surveillance, however, without the public health and other concerns that arise from a cancer label.