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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
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