Ryan Hutchinson, MD

 standardization of management will be a key component of quality data going forward, says Scott Eggener, MD.

Dr. EggenerWith the ever-increasing focus of non-radical management of low-risk prostate cancers, the topic of focal therapies is a rapidly evolving one. At the 2016 Society of Urologic Oncology annual meeting in San Antonio, Dr. Eggener provided an overview of focal therapies for prostate cancer. He reviewed the current landscape of prostate cancer screening and treatment, conceptual issues with focal therapies, and current organizations’ consensus statements on these therapies.

	Focal therapies for prostate cancer offer the potential advantages of decreasing cancer mortality with the potential of sparing the morbidity of more radical treatment options like prostatectomy or radiation. They also have the potential to be subject to the same concerns that these modalities face, namely over-diagnosis and overtreatment of otherwise indolent cancers.

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	Dr. Eggener, associate professor of surgery at the University of Chicago Medical Center, discussed balancing the prostate cancer mortality advances seen since the advent of PSA screening with the need to screen selectively, knowing when to stop screening, and knowing when to appropriately use active surveillance and focal therapies.

	With respect to focal therapy being counter to past and current dogma of cancer management, Dr. Eggener pointed out other techniques for managing urologic cancer that were initially met with strong resistance. For example, initially skeptical views of minimally invasive surgery, active surveillance, monitoring of the post-chemotherapy retroperitoneum, and enucleation versus conventional partial nephrectomy have all since changed. Similarly, the use of lumpectomy in breast cancer faced fierce resistance early on, but was eventually backed by both high-quality data and general consensus in the medical community, he said.

	Several consensus statements have been published in the field of focal therapy and provide a preview of what to expect in focal therapy research going forward, Dr. Eggener said. Specifically, he discussed an international multidisciplinary consensus statement published in 

 and a report from a Delphi consensus project published in the 

 Specifically, standardization of management will be a key component of quality data going forward, with recommended inclusion criteria for clinical trials of a PSA <15.0 ng/mL, life expectancy >10 years, and Gleason grade 3+3 or 3+4 as a standard.

	Dr. Eggener also offered some standardized definitions of success and failure for data going forward: In-field failures were defined as a higher local Gleason grade, persistence of similar grade cancer (including those undergoing repeat ablation), and use of additional, more radical, management strategies. Out-of-field failures were defined as generally selection failures or representative of cancer progression.

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	Intermediate-risk cancers are generally ideal for study in focal therapy, Dr. Eggener surmised. Magnetic resonance imaging-targeted biopsies are recommended to plan treatment; untreated foci of low-grade, indolent cancers are acceptable; and the final word on the value of focal therapies would come from high-quality data sets, he said.

	Dr. Eggener closed his talk with a quote from Bernard Fisher, MD, the pioneer of the lumpectomy in breast cancer management: “Scientific method trumps empiricism, anecdotalism, and inductivism.” Dr. Eggener then shared his own addition: “But don’t underestimate market forces, longstanding habits, influence of industry, politics, and profit motives.”

	Dr. Eggener is a consultant for NxThera and a consultant/investigator for Profound Medical.

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In the arena of focal therapy for prostate cancer, standardization of management will be a key component of quality data going forward, says Scott Eggener, MD.

Prostate Ca focal therapy’s value awaits high-quality data

Atypical histologic variants of bladder cancer are rare, comprising 5% or less of urothelial carcinomas. Atypical tumor subtypes are associated with later stage of diagnosis and worsened clinical outcomes when compared to the standard histologic variant.

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	In a general session at the 2015 Society of Urologic Oncology annual meeting in Washington, Gopa Iyer, MD, of Memorial Sloan Kettering Cancer Center, New York, presented his work analyzing the genetics of two variants-plasmacytoid and adenocarcinoma-and the possible implications of these findings for clinical practice.

	Plasmacytoid urothelial carcinoma is generally chemoresistant with peritoneal spread and a high rate of local recurrence after surgery.

	"Histologically, it is similar to mammary lobular carcinoma and diffuse gastric carcinoma, with frequent inactivating mutations in E-cadherin,” Dr. Iyer said. He then presented representative histology showing similar morphology between these tumors and plasmacytoid urothelial carcinoma (figure).

	Using targeted exon capture, Dr. Iyer and colleagues evaluated 31 plasmacytoid variant tumors and found 23 had cadherin 1 truncation mutations and three had point mutations. In those plasmacytoid tumors without obvious exon mutations, the researchers examined the methylation status of the cadherin promoter region with bisulfide sequencing and found increased methylation in four of five normal exon promoter regions.

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	In total, their results would suggest a strong role for E-cadherin expression loss in the morphology and pathophysiology of plasmacytoid urothelial carcinomas. This hypothesis was further examined by taking known urothelial carcinoma cell lines and knocking out CDH1 expression. Two physical tests were then performed: a “scratch” test assaying the cell line’s ability to reform a cell sheet and a Boyden permeability assay assessing the ability of the cells to penetrate a standardized membrane. In both assays, the cells displayed differential activity compared to parietal cell lines, further supporting the hypothesis.

	Dr. Iyer then turned his attention to another urothelial carcinoma subtype: adenocarcinoma. Adenocarcinomas can arise both from the bladder proper and from the urachus. As with other infrequent subtypes, they are often found at an advanced stage. Similar to gut-based adenocarcinomas, they are responsive to 5-FU-based chemotherapy in the metastatic setting, although prognosis is poor after progression.

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	Using exon capture sequencing, Dr. Iyer and and colleagues examined 16 primary bladder adenocarcinomas and 10 urachal adenocarcinomas. They found similar alteration frequencies in both categories of adenocarcinomas but more frequently found KRAS mutations (34% versus 2%) and less frequently found FGFR3 and KDM6A mutations (0% and 3% vs. 19 and 25%, respectively) when compared to standard urothelial carcinomas.

	Two non-genitourinary tumor types with similar E-cadherin alterations and histologic morphology to plasmacytoid urothelial carcinomas. (Images courtesy of Gopa Iyer, MD)

	Using these genetic observations, Dr. Iyer then reported on a patient treated at Memorial Sloan Kettering with metastatic urachal adenocarcinoma who underwent tumor exon sequencing that revealed GNAS and KRAS alterations. This led his physicians to trial therapy with trametinib (Mekinist), a targeted MEK inhibitor with approved indications in melanoma. To date, Dr. Iyer reports the patient has had 18 months of radiographically stable disease while on therapy.

	Dr. Iyer closed his talk by reviewing two main points. He noted loss of E-cadherin expression was frequently found in plasmacytoid variant bladder cancers and that a mechanistic link likely exists for this tumor’s enhanced local migration and aggressiveness. In addition, urothelial adenocarcinomas are genomically similar to colorectal adenocarcinomas, and frequent MAPK pathway alterations may offer a therapeutic target with MEK inhibition, he said.

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Urology Times SUO internship program member Ryan Hutchinson, MD, reports on a presentation on plasmacytoid urothelial carcinoma and adenocarcinoma.

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Economic conditions and insurance status appear to predict 

 diagnosis and management, according to a study presented at the 2015 Society of Urologic Oncology annual meeting in Washington. 

	The effect of the economic downturn of 2007-2009 on daily life was profound for many Americans. Less is known about how it affected the diagnosis and management of urologic cancers. Weiner et al from the University of Chicago hypothesized that during a time of resource scarcity such as the “great recession” from December 2007 to January 2009, the incidence of PSA-detected prostate cancer (cT1c) would decrease and the use of noncurative management strategies (such as active surveillance) would increase.

	Using the Surveillance, Epidemiology, and End Results (SEER) cancer database, the authors compared macroeconomic factors such as per capita income, Standard and Poor (S&P 500) Index closing, inflation rates, and unemployment rates versus incidence and management of prostate cancers. They defined men managed with an initial conservative approach as those without surgery or radiation coding within 1 year of diagnosis.

Next: Positive correlation between per capita income and PSA screen-detected PCa incidence

	Using a multivariate linear regression model, lead author Adam Weiner and colleagues found a positive correlation between per capita income and PSA screen-detected prostate cancer incidence (coefficient 79, 95% CI: 40.3 to 118, 

<.001) and a trend toward significance for a correlation with S&P 500 closings (coefficient 5.18, 95% CI: –0.36 to 10.7). They also found significant correlations between use of initial conservative management and the negative economic indicators of unemployment rate (coefficient 78.3, 95% CI: 56.3 to 100.3, 

<.001) and inflation rate (coefficient 28.6, 95% CI: 5.13 to 52.1, 

	On multivariate analysis, they identified additional socioeconomic trends, including increased use of conservative management in non-Hispanic African-Americans (HR 1.74, 95% CI: 1.64-1.85, 

<.001) and in older patients with yearly age as a continuous variable (HR 1.03, 95% CI: 1.03-1.04, 

<.001). Those patients with intermediate- and high-risk prostate cancers were significantly less likely to undergo conservative management than those with low-risk disease 

<.001 for both). Similarly, those with Medicaid insurance or no insurance were also less likely to undergo initial curative intent therapy at all time points 

	The authors then plotted personal income per capita versus new diagnoses of PSA-detected prostate cancer and showed a correlation with more men diagnosed as personal income increased (figure).

	The authors concluded that the data set supported their original hypotheses; specifically, that during lean economic times fewer prostate cancers are screen diagnosed and those that are diagnosed are more likely to be conservatively managed. They also noted that being on public assistance insurance (Medicaid) or being without insurance similarly increased the likelihood that prostate cancer was managed conservatively.

	Discussing the implications of the findings, Weiner said, “Prostate cancer screening and definitive treatment are subjects of controversy with questionable efficacy and increased cost. Thus, faced with financial insecurity, patients or practitioners may elect less expansive screening or treatment for prostate cancer, in aggregate.”

	“To summarize our results, the incidence of cT1c prostate cancer correlated positively with national monthly income per capita, which should increase in times of a thriving economy, and negatively with inflation, an increase in which is associated with decreased financial security. Use of conservative management correlated positively with unemployment, an increase in which is associated with financial insecurity,” added Weiner, who worked on the study with Scott Eggener, MD, and Rena Conti, PhD.

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Researchers hypothesized that during a time of resource scarcity, the incidence of PSA-detected prostate cancer would decrease and the use of noncurative management strategies would increase, reports Urology Times SUO internship program member Ryan Hutchinson, MD.

Author | Ryan Hutchinson, MD

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