Why Is My Patient Dying If He Only Had a Gleason 3+3?

I have been struck in the past few weeks by the number of patients in my practice who have advanced metastatic CRPC who were diagnosed more than 15 years ago and had, on their original biopsy specimen, ONLY a Gleason 6 pattern prostate carcinoma.

Yes, it happens. And I seem to be experiencing a run of them.

Two patients I saw in the last week in fact were diagnosed with localized prostate cancer in the early 1990’s, (I was in the first couple years of medical school at that time), one was even diagnosed in the 1980’s. One was diagnosed in 2000. All long before I started practice here.

One long-term and dear patient recently initiated hospice with mCRPC. As we said our good byes’ I was struck not only by the long time I had cared for him in the clinic (almost 14 years) but also the biological questions his story raised.  He had a Gleason 6 diagnosed in 1999 and never received definitive local therapy ( and refused it when it was offered later). His initial treatment, which sufficed for disease control for over a decade, was intermittent ADT, but eventually he developed the mysterious entity of non-metastatic CRPC, then bonafide metastatic CRPC. Now, at the age of 83, he faced a decision to receive docetaxel or not, and he chose not,  and is home on hospice, content with the decision.

And yet this occurs at a time as the prostate cancer community, myself included,  is engaged in a legitimate and thoughtful debate as to whether Gleason 6 should be reclassified as something other than cancer.1

So what is going on here?

First, attacking the clinical perspective. These patients stand out in the memory of GU medical oncologists like myself because we have known them for so long. It’s a type of recall bias. And by the way I didn’t just notice his Gleason 6 tumor on the day when he left my practice for hospice care. I’ve been struck by watching his disease course for many years. His case, like many others, has been marked by general slow progression and good durations of response to various therapies like ADT, the addition of Bicalutamide, and Abiraterone.

We have done numerous subset analyses of therapy with Abiraterone, for example, that show that higher Gleason score patients are more likely to experience drug resistance and death from the disease. Of course, such findings could also be viewed from the inverse perspective: the low Gleason score patients do well on almost any treatment for prostate cancer that we administer, from Provenge to Abiraterone to Docetaxel.2

Twenty-five years is a long time and not many clinical trials or outcomes databases have been extant enough time to contain many registrants who have made it to the quarter century landmark following time of diagnosis of a disease that is generally felt to be confined to ‘older’ men. Add to that the fact that the PSA test is still less than 30 years old and what you have is a very small number of individuals who were diagnosed in the 1990s with a Gleason 3+3=6, have not died of other causes, and remain under our care for prostate cancer. 

But it does challenge the assertion I have heard that men don’t die of a Gleason 6 tumor, and the foundation of the argument that it should stopped being called a ‘cancer’. 

One perspective to consider are the shifting sands in the pathology community. Quite possibly, if I dug up my patient’s first prostate biopsy and had it re-analyzed, there could be some Gleason 7 or higher tumor that was missed. In particular less experienced pathologists or those who see fewer prostate cancer cases commit such omissions – or perhaps were more likely to back in the 90s. Or maybe it was there but not missed by the pathologist, but missed by the biopsy needle. 

But let’s assume that pathologists are right most of the time, which they probably are. In this case, a potential outcome is that untreated low grade tumors progress to a higher grade tumor.

Another perspective is that the Gleason 6 was truly NOT destined for progression, but that the same genetic background that allowed the Gleason 6 would’ve allowed for the emergence of a separate Gleason 7 or 8 or 9 that would’ve become clinically significant and even life threatening. Put another way, the Gleason 6 is not the problem, but it is a hallmark of a biological / genetic prostate epithelial background that could become one.

Both scenarios support PSA screening, active surveillance and the integration of a risk adapted therapeutic approach – with a definite emphasis on the word ‘active’. 

But neither scenario supports treatment mediated selection pressure as the underlying biological paradigm behind tumor lethality. And in my opinion, at least, treatment mediated selection pressure is what is behind the resistant tumors I am seeing in my other patients. In other words, it is the treatment that is contributing to lethality, not the Gleason grade. 

All leading to a provocative question ( that I am frequently asked even by patients): Does starting ADT early in a patient with a Gleason 6 merely give the tumor an opportunity to adapt to the low androgen milieu and become resistant to it?

In other words -  If Gleason 6 is a truly indolent cancer, could not treating it result in outcomes that are not only not worse than, but better than, if we did treat it? 

Did the treatment with primary ADT that my patient started so many years ago actually induce a selection pressure in his tumor that is now leading to his demise?

Treatment mediated selection pressure is the force by which tumors adapt, survive and progress through the outgrowth of cells harboring mutations, sensitivity to survival stimuli or other forces that have resulted in them not being killed by the therapy administered to the patient. It’s not a term that is in common use, and yet it is the driving force behind the lethality of prostate cancer. Even perhaps the Gleason 6 that isn’t supposed to be deadly.

Early ADT  - by stressing the tumor – may give remaining malignant cells time to adapt, mutate and amplify their way to treatment resistance and lethality. 
So in the end, is my 83-year-old patient heading peacefully off to hospice doing so now in spite of the treatment that I gave him, or because of it?

I wasn’t practicing in the late 1990’s when it was first suggested that he received primary ADT as his only treatment and, all things considered, he hasn’t really ‘suffered’ much from prostate cancer, but now is experiencing more fatigue and a decline in his performance status as he has developed progressive nodal and bone metastases. 

To be lethal, prostate cancer seems to benefit from treatment mediated selection pressure. Without the treatment, and thus without the selection pressure, would a Gleason 6 be killing my patient?

Written by: Charles Ryan, MD, B.J. Kennedy Chair in Clinical Medical Oncology, Director and Professor of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota

Published Date: May 1st, 2017

1. Carter, H. Ballentine, Alan W. Partin, Patrick C. Walsh, Bruce J. Trock, Robert W. Veltri, William G. Nelson, Donald S. Coffey, Eric A. Singer, and Jonathan I. Epstein. "Gleason score 6 adenocarcinoma: should it be labeled as cancer?." Journal of Clinical Oncology 30, no. 35 (2012): 4294.

2. Fizazi, K., T. W. Flaig, M. Stöckle, H. I. Scher, J. S. de Bono, D. E. Rathkopf, C. J. Ryan et al. "Does Gleason score at initial diagnosis predict efficacy of abiraterone acetate therapy in patients with metastatic castration-resistant prostate cancer? An analysis of abiraterone acetate phase III trials." Annals of Oncology 27, no. 4 (2016): 699-705.

Additional reading by Charles Ryan: 

Introducing the Virility Triad

ADT and Depression: What do we know, what do we not know?