In 2009, an article on the single-cell theory of prostate cancer metastasis appeared in the journal Nature. There was little fanfare, but it might have been better met with a trumpeted announcement. Why? Because it supported the theory that some prostate cancer cells are more lethal than others—and this has tremendous implications for treatment choices.
Let’s back up. From the time prostate cancer was recognized as a disease—as far back as the ancient Egyptians—it was presumed to be the same disease in every man who developed it. For centuries, nothing could be done about it. In fact, surgery to remove the prostate and the cancer it held did not really come into being until less than a century ago. At the time, radical prostatectomy as an open surgery involved risk of blood loss, painful recovery, and a significant likelihood of long term urinary, sexual and even bowel side effects. Within the last 20 years, the addition of laparascopic and robot-assisted approaches contributed to less collateral damage with faster recovery. When the removed glands were sent to the pathologist for inspection, microscopic cancer cells were often found in other gland locations besides the primary tumor. Prostatectomy became the gold standard of treatment because it had the longest statistical data, and the idea of this disease being multifocal (many locations) was reinforced by the evidence. No one was asking whether some cases were unifocal, and genetic analysis did not yet exist.
Thus, prostate cancer was approached as if all cases were created equal.
If this were true, then it would be in a patient’s interest to err to the side of caution and have a radical (whole gland) treatment in order to preempt the possible spread of prostate cancer. The problem is, all prostate cancer cells apparently do not behave identically. In fact, a single lethal cell may play a key role in spreading prostate cancer beyond the gland. The 2009 article in Nature demonstrated that metastatic prostate cancer appears to start with a single parent cell that copies itself, leading to more and more copies. Thus, regardless of the number of unique sites in which the cancer appears (e.g. bone and liver in the same patient), they trace their roots back to a single cell.[i] This is called “monoclonal” cancer (“mono” means single or sole, and “clonal” means able to copy itself.) The authors discovered that metastatic tumors in various locations were genetically identical within that patient.
This adds validity to the theory that some prostate cancer is “significant disease,” meaning more likely to become life-threatening, while “insignificant disease” may be safely monitored as they may never turn into a life-threatening disease. In fact, research since the early 1990s suggests that the largest tumor in cases of multifocal cancer is the “index lesion” most likely to develop dangerous aggressive cells.[ii],[iii],[iv]
It is precisely this new knowledge that generates interest in focal ablation of prostate tumors. Researchers in pathology labs have brought evidence to the table that not all prostate cancer is multifocal throughout the gland. It is this evidence that generated research into the use of MRI guidance to biopsy directly into a tumor, and its use to deliver a minimally invasive and precise lethal energy source to a tumor most likely to contain that lethal cell. In fact, focal therapies are successfully delivering cancer control at rates equivalent to prostatectomy, but with far fewer side effects. Furthermore, imaging can be used to monitor for cancer recurrence following treatment.
The article in Nature was timely. It roughly coincided with published evidence from pathologists that some prostate tumors appear to be truly unifocal, and that even if there are other microscopic sites, it is the primary (largest) tumor that likely contains the single dangerous parent cell. This evidence supports MRI-guided biopsy as a way to sample accurately from the core of a tumor where the ever-mutating cancer cells may be incubating that lethal cell that can clone itself. If clinicians have a high degree of confidence that the pathology report is accurate, they can work with patients on determining on whether a whole-gland vs. focal treatment is in the patient’s best interest.
It seems we are at the dawn of a new era in prostate cancer management strategies. By asking fresh questions and thinking in different ways, we can look for breakthrough clues that not all prostate cancers need to be radically treated. The authors of the Nature article on monoclonal metastasis have made a tremendous contribution to the future of prostate cancer diagnosis and treatment.
[i] Liu W, Laitinen S, Khan S et al. Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer. Nature 2009 May;15(5)559-64.
[ii] Villers A, McNeal JE, Freiha FS, Stamey TA. Multiple cancers in the prostate. Morphologic features of clinically recognized versus incidental tumors. Cancer. 1992;1(70):2313–2318.
[iii] Noguchi M, Stamey TA, McNeal JE, Nolley R. Prognostic factors for multifocal prostate cancer in radical prostatectomy
specimens: lack of significance of secondary cancers. J Urol. 2011;170:459–463.
[iv] Stamey TA, McNeal JE, Yemoto CM, Sigal BM, Johnstone IM. Biological determinants of cancer progression in men with
prostate cancer. JAMA. 1999;21(15):1395–1400.