Multifocal prostate cancer
In the not-too-distant past, medical schools taught young urologists that all prostate cancer (PCa) is multifocal – scattered throughout the gland. The belief was, “If you find it in one place, it must also be in other places even if undetectably small.” As a result, they carried this belief into their clinical practice and were biased toward whole gland surgery (radical prostatectomy) or total gland radiation (external beam or seed implants). Of course, Watchful Waiting (WW) was also an option, but usually reserved for patients who were a) old enough to have less than 10 years life expectancy, b) Gleason 3+3 patients, or c) not good candidates for surgery or radiation.
As it turns out, as many as 40% of newly diagnosed PCa patients have unifocal disease, that is, just one focus of cancer. But that still leaves 60-80% of patients with multifocal PCa. Without evidence to the contrary, multiple foci in the same gland were thought to be biologically homogeneous, that is, identical to each other. Even if that weren’t so, it wouldn’t matter if the whole gland was going to be treated anyway. “We’ll just get all the cancer out and you won’t have to worry about it,” was the philosophy.
Then, along came the tools to analyze PCa at the molecular level, bringing new knowledge of the biology of PCa.
Prostate biopsy may not tell the whole story
At the June, 2017 annual meeting of the American Society of Clinical Oncology, an important paper on tissue expression-based prognostic tests was presented by Dr. Simpa Salami.[i] This means analysis of tissue samples to obtain their DNA and RNA genomic sequencing (a sort of genetic signature that marks a PCa cell line). These signatures are called biomarkers because are distinguishing biological features that mark one cell line vs. another. What Dr. Salami and his colleagues found is that biopsy samples alone are not always enough to give a complete picture of an individual patient’s disease—and the picture can be quite complicated.
New evidence suggests genetic differences can co-exist
Dr. Salami’s team found that when more than one focus of disease is present in the same prostate, there can be significant genomic differences among foci. They analyzed the cases of 14 patients for whom they had both biopsy tissue samples, and post-prostatectomy gland and lymph node specimens. In other words, they could compare what the biopsies found with the actual whole glands and lymph nodes to identify all possible biomarkers.
They discovered that it was possible to have significant DNA differences among cells within the same primary tumor from an individual patient. When they analyzed RNA in the various tumors, it was apparent that foci with low-grade (low risk) cell lines tended to cluster together, and were separate from those with high-grade (aggressive) foci. Thus, the same patient could be harboring at least two genomically distinct cell lines in his gland.
Perhaps more alarming is the evidence from the 10 patients who were found to have lymph node involvement at the time of their surgery. One would expect that “breakaway” tumor cells that are able to travel from the prostate to the nearby lymph nodes would come from the most dangerous tumor in multifocal disease: either the largest tumor, or a small tumor harboring high-grade PCa. This proved not entirely accurate.
This study linked tumors closest to the gland margin with lymph node spread, rather than more interior tumors. However, those more peripheral tumors were “not necessarily the largest primary lesion or the one with the highest Gleason score.”[ii] This is a surprising find. The authors refer to the disease focus having the greatest ability to spread as the “biologically dominant lesion,” and so it would seem.
Finding the biologically dominant lesion in multifocal PCa
Clearly, heterogeneous multifocal disease is a challenge because it’s not all equally predictable. Since the biopsy alone is not sufficient to paint a full picture, it’s hard to develop a prognosis (projected outcome) of how one patient’s multifocal disease is likely to behave. It’s essential to identify which multifocal patients may be more prone to metastasis.
The research team plans to recruit 50 patients for a new study to learn if MRI (magnetic resonance imaging) can help reveal the biologically dominant tumor. Also, circulating tumor cells in blood, as well as PCa cells found in urine, may “reflect the heterogeneity of multiple foci within the prostate,”[iii] which could help avoid unnecessary biopsies.
This and studies like it are extremely important. Learning about biologically dominant lesions and tracking their behavior may help us understand why nearly a quarter of prostatectomy patient experience recurrence even though the surgeon was sure he “got it all.” It will greatly help in treatment decision-making and planning. If the “time bomb” tumors can be identified and located before metastasis begins, many men can be spared the disappointment of finding out their cancer had spread. In short, this type of research is doing a huge favor for PCa patients everywhere.
[i] Krader, Cheryl Guttman. “Tissue-based PCa assays not robust to focality.” Urology Times, Dec. 1, 2017. http://urologytimes.modernmedicine.com/urology-times/news/tissue-based-pca-assays-not-robust-multifocality?page=0,0