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6 of 8 | JNCI J Natl Cancer Inst, 2016, Vol. 108, No. 4 news hormones and other molecules that affect glucose metabolism and tends to have higher levels of inflammation, according to Rachel A. Murphy, Ph.D., of the School of Population and Public Health at the University of British Columbia in Vancouver. In a study under review, Murphy’s lab has dissected the pathways that link specific adipose depots and metabolic deregulation. Her team looked for metabolites in the blood in relation to subcutaneous, visceral fat and to overall body mass index to try to identify causal metabolic factors. One fat depot that has been carefully dissected is the white adipose tissue of the breast. Andrew Dannenberg, M.D., associate director of cancer prevention at the Sandra and Edward Meyer Cancer Center at Weill Cornell Medical College in New York, and colleagues found that inflamed white adipose tissue of the breast occurs in most obese women with breast cancer and is associated with increased levels of aromatase, the ratelimiting enzyme for estrogen biosynthesis (Cancer Prev. Res. 2011;4:1021–9). That local effect of inflammation and aromatase expression in fat tissue is thought to promote cancer progression in women with breast cancer and may be a marker of breast cancer risk. “Aromatase is as well-vetted a target in breast cancer as one can imagine. Large trials have shown women at high risk of breast cancer who take an aromatase inhibitor have as much as a 50% reduction in risk,” Dannenberg said. Systemic metabolic syndrome also has been linked to increased breast cancer risk, but “exactly why is unclear,” Dannenberg said. Tying the initial demonstration of local breast tissue inflammation to systemic metabolic factors, Dannenberg’s lab showed that about half of the 100 women with early-stage breast cancer who have white adipose inflammation in the breast also had elevated insulin, glucose, triglycerides, and other markers of metabolic syndrome. In a second cohort of 127 women, inflammation was associated with a worse course of disease for women who go on to develop metastatic breast cancer (Clin. Cancer Res.; doi:10.1158/1078-0432. CCR-15–2239). “This leads us to postulate that inflammation may be critical for understanding the established link between metabolic syndrome and breast cancer risk,” Dannenberg said. “However, if inflammation has multiple effects including contributing to insulin resistance, then anti-inflammatory strategies to reduce risk may be more effective than simply targeting insulin.” Because the cause of breast cancer in normal-sized women is uncertain, Dannenberg is investigating both adipose inflammation and aromatase levels in metabolically obese but normal-sized women because he believes occult breast adipose inflammation may be a key driver of breast cancer risk in those normal-sized women. His lab also has begun an effort to develop metabolic markers that could reflect both inflammation and aromatase levels to noninvasively gauge breast cancer risk. Many others are following suit to find both markers of risk and ways to reduce that risk. “I think we have well established the connection between obesity and cancer. We are now moving away from proving the connection to asking, ‘How do we disconnect the link?’” Hursting said. © Oxford University Press 2016. First published online April 2, 2016 DOI:10.1093/jnci/djw116 Active Surveillance Gets Personal By Charlie Schmidt Active surveillance is fast becoming a standard management practice for some men with prostate cancer. Instead of being treated immediately for slow-growing tumors that may never become life threatening, men on active surveillance have their cancers monitored routinely and undergo treatment only if the disease begins to spread. Long-term studies attesting to its safety have helped to propel active surveillance from a nexus in academic centers into the broader community. The two largest studies monitored a nearly 2,300 men on active surveillance for up to 15 years. Cancer-specific survival rates were 95% or higher in the lowest risk categories. Both studies appeared in the Journal of Clinical Oncology. The first was in December 2014 by Laurence Klotz, M.D., and colleagues from the Sunnybrook Health Sciences Centre in Toronto, Canada; the second was in October 2015 by Jeffrey Toisian, M.D., and colleagues from Johns Hopkins Medicine in Baltimore. The question now is whether the high survival rates observed in the studies are broadly applicable, especially to younger healthier men with few life-threatening comorbidities, or to black men who are more likely to die from prostate cancer than men of other races. “Active surveillance shouldn’t be seen as a one-sizefits-all approach,” said Anthony D’Amico, M.D., Ph.D., an oncologist and professor at Harvard Medical School in Boston. “But it’s expanding across the board irrespective of race, age, and health status and that worries me.” D’Amico and others are now working to personalize active surveillance by refining the criteria used in selecting the best candidates. Men have traditionally been selected according to just a few factors: Gleason scores, prostate-specific antigen (PSA) levels, and the number of positive biopsy cores. According to D’Amico, a man’s age, ethnicity, and additional comorbidities, as well as results from magnetic resonance imaging (MRI) and molecular testing, should also be taken into account when deciding whether active surveillance is a wise choice for a particular patient. Jonathan Epstein, M.D., a pathologist and professor at Johns Hopkins Medicine who directs that institution’s long-standing active surveillance program, agrees. “Our first enrollment criteria were developed to generate results for a very restricted group of the lowest-risk patients that would be acceptable to the medical community,” he said. “Now we’re tailoring our approach so that it’s more individualized and inclusive of a broader range of patients.” An Evolving Process Johns Hopkins Medicine helped to pioneer active surveillance in the United States with a program launched in 1995 geared to men categorized as having very low-risk prostate cancer. Those patients have at most two positive biopsy cores with no more than 50% tumor involvement, Gleason scores no higher than 3 + 3 = 6, and a PSA density (i.e., PSA level divided by prostate volume) of 0.15 or less. According to Epstein, limiting the program to very low-risk patients minimized the chances of undertreatment at a time when active surveillance was viewed with broad skepticism. “Everyone was being treated for prostate cancer back then and active surveillance was a foreign concept,” he said. “We needed positive results to bolster its credibility.” The Sunnybrook program, also launched in 1995, took a more inclusive approach by accepting “favorable risk” (i.e., low and low-end intermediate risk) patients with Gleason scores of either 6 or 7 and PSA levels of 10 ng/mL or higher. Klotz said the more relaxed entry criteria were designed to avoid unnecessary treatment as much as possible. “It was a classic medical trade-off,” he said, “by which many more patients could avoid the side effects of therapy with the price of slightly higher prostate cancer mortality rates.” The differences in approach are evident in the follow-up data: After 15 years, 1.5% of the 993 patients enrolled into Sunnybrook’s active surveillance cohort had died of prostate cancer, and 3% had prostate cancer metastases, whereas fewer than 1% of 1,298 patients in the Johns Hopkins cohort had died from either primary or metastatic prostate cancer over the same duration. According to Klotz, most men who died from prostate cancer in the Sunnybrook cohort were initially diagnosed with Gleason 7 cancer. The rest had been diagnosed as Gleason 6 when more dangerous tumors lurked in the anterior prostate, which isn’t as accessible to standard ultrasound-guided biopsy. Klotz said that Gleason 6 cancer is nonmetastatic and usually doesn’t require treatment. But he added that up to a third of all men diagnosed with Gleason 6 cancer on standard biopsy have a higher-grade tumor hidden somewhere in the prostate. New and emerging technologies, especially multiparametric MRI (mpMRI), have allowed the Sunnybrook and Johns Hopkins programs to evaluate potential candidates with better clarity. According to Klotz, mpMRI of the prostate “can tell you with 95% confidence whether or not a man has significant cancer.” He added that Sunnybrook now mandates mpMRI for all potential candidates with evidence of Gleason pattern 4—a worrisome finding that elevates the overall diagnosis to at least Gleason 7—on ultrasound-guided biopsy. Johns Hopkins, meanwhile, now leans toward a more inclusive selection that allows for some low-risk (as opposed to very low risk) patients with four positive cores on initial biopsy, but in these cases it also requires mpMRI to confirm the absence of more aggressive cancer. “Active surveillance shouldn’t be seen as a onesize-fits-all approach. But it’s expanding across the board irrespective of race, age, and health status and that worries me.” Managing Risks in African Americans Both Klotz and Epstein said that black men, who are poorly represented in both cohorts, pose unique challenges for active surveillance. About 45% of black patients diagnosed with prostate cancer harbor occult high-grade disease, compared with 30% of white patients, “so we scrutinize blacks more carefully with a risk-adapted approach,” Klotz said. “We make sure they all get an MRI and a confirmatory biopsy.” Klotz and Epstein said they also rely increasingly on molecular assays—especially the Oncotype DX and Prolaris genomic tests—as diagnostic aids that can help to rule out occult metastases in black men considering active surveillance. Epstein said he’s generally hesitant to recommend active surveillance for African Americans, with their propensity to harbor anterior high-grade tumors. The probability of diagnosing low-risk cancer in white patients correctly with a standard biopsy and a PSA measure is about 80%, he said, “whereas with African Americans it’s flip of the coin.” Epstein added “On an African American candidate we would use mpMRI up front to rule out an anterior tumor after an initial positive biopsy, whereas on a [white candidate] we might not do that on initial review. We would still follow both groups of men closely with repeat biopsies that are variably timed depending on a man’s clinical and pathological findings.” Epstein said that since neither Klotz nor Epstein reported comorbidity data, it’s not possible to ascertain the degree to which men in the cohorts (aged an average of 66 years at diagnosis) might have been unhealthy t o b eg i n w i t h and thus more likely to die from causes other Anthony D’Amico, t h a n p ro s t a t e M.D., Ph.D. cancer. “Active surveillance in otherwise healthy, young patients may not reproduce the low prostate cancer death rates reported in the studies,” he said. Klotz and Epstein responded that their cohorts generally were healthy. And Klotz in particular said that whereas older, sicker patients are less likely to die of prostate cancer, quality of life benefits from active surveillance—namely, preserved sexual potency—matter more to young healthy men. Researchers including Epstein are now developing risk assessment tools to predict optimal benefit from active surveillance on the basis of a variety of individualized factors. “We want to consider a wide range of parameters so we can make the most informed decisions,” said Lisa Loeb, M.D., a urologist and prostate cancer specialist at New York University. “And we should also incorporate patient preference since that has a profound influence on perceptions of benefits and harms from treatment. All these considerations should inform the best course of action.” © Oxford University Press 2016. First published online April 2, 2016 DOI:10.1093/jnci/djw114 news NEWS | 7 of 8