NEWS IN BRIEF
AUGUST 2016�CANCER DISCOVERY | 809
adds. For example, SOS1 was already
known to be mutated in patients with
Noonan syndrome, a genetic disorder,
but previous smaller studies failed to
identify it in lung ADCs.
The team also found that 47% of lung
ADC and 53% of lung SCC samples
had at least fi ve neoepitopes—peptides
arising from somatic tumor muta-
tions—that could potentially be targeted
by cancer vaccines. The identifi cation
of these neoepitopes suggests that in
NSCLC, a signifi cant fraction of tumors
may respond to immune checkpoint
inhibitors, Meyerson observes.
Additionally, he says, this study
shows that the two main NSCLC
subtypes are more distinct than previ-
ously thought. Of 38 mutated genes
detected in the lung ADC samples, and
20 detected in lung SCCs, only six were
shared by both subtypes. In fact, the
mutations and amplifi cations noted
in lung SCC were found to be more
similar to other cancers associated with
smoking—including head and neck SCC
and bladder cancer—than to lung ADC.
“It indicates that there are some very
similar pathway abnormalities and
mutations that accompany squamous
cell tumors, regardless of where they
originate,” says Stephen Baylin, MD,
co-director of the cancer biology research
program at the Sidney Kimmel Com-
prehensive Cancer Center in Baltimore,
MD. “As such, there may be common
management strategies that could be
used to treat these types of cancer.”
Further research is needed into
the role of neoepitopes in immuno-
therapy, Meyerson notes. “We need to
understand the relationship between
neoepitopes, especially recurrent ones,
and patient responses to immune
checkpoint inhibitors,” he says. “Future
studies should seek to determine
whether predicted cancer neoepitopes
are in fact leading to immune responses
in lung cancer.” –Janet Colwell ■
Single-Agent Abemaciclib Active in Breast Cancer
Results from a phase II study
indicate that abemaciclib (Eli Lilly),
an investigational CDK4/6 inhibitor,
demonstrates single-agent activity in
women with advanced HER2-negative,
ER-positive breast cancer whose disease
has progressed on endocrine therapy
The project’s investigators, led by
Nikhil Wagle, MD, a medical oncolo-
gist at DFCI, aim to create a repository
of mineable data to speed breast cancer
genomics research, better understand
drug resistance, and provide leads for
the development of new therapies.
To that end, trial participants, all of
whom have metastatic disease, agreed
to share their medical records with
investigators, provide saliva samples
for the extraction of germline DNA,
and make their tumor tissue available
for next-generation sequencing.
Roughly 85% of patients with breast
cancer are treated in community set-
tings, where their tissue samples are
collected only for initial diagnosis,
then stored and not routinely made
available for research, Wagle said.
Until now, “no one has asked if they’d
be willing to share [their samples] with
researchers for discovery.”
Joanne Mortimer, MD, director
of the women’s cancers program at
City of Hope Comprehensive Cancer
Center in Duarte, CA, who is not
involved in the project, described it as
“brilliant.” Patients want to contribute
their data so they can better under-
stand their own disease and help
others, she said. “Nobody wants to feel
like they’ve died in vain.”
To date, most of the project’s par-
ticipants are white women, Wagle said.
He has started additional outreach
efforts with advocacy groups to diver-
sify the patient cohort.
“We should be able to reach lots of
different people who haven’t been stud-
ied using traditional approaches,” he
said. Gathering data from patients of
different racial and ethnic backgrounds
will help fi ll gaps in knowledge, such
as why black women with breast cancer
have poorer outcomes than whites.
The power of such patient-driven
research, Wagle said, is that it pools
data and identifi es “rare” patients—for
instance, those who carry an uncom-
mon mutation, are younger than
typical patients, or have an exceptional
response to a particular therapy. These
data, which can be challenging for sci-
entists at any one institution to obtain,
will be shared (identifying informa-
tion removed) with the NIH and the
broader cancer research community.
“I think that Dr. Wagle has really
established a paradigm that we can
apply across other cancer types,” said
Sumanta Kumar Pal, MD, co-director
of the kidney cancer program at City
of Hope. “He should be commended
for developing a platform that allows
for very rapid collection of data.”
–Karen Weintraub ■
New Driver Mutations Detected in NSCLC
A comprehensive genomic analy-
sis of non–small cell lung cancer
(NSCLC) has identifi ed additional
driver mutations that may guide the
development of new targeted drugs
and immunotherapy. The fi ndings
also highlight key differences between
subtypes of NSCLC that could inform
future therapeutic management strate-
gies (Nat Genet 2016;48:607–16).
The study researchers profi led two
major subtypes of NSCLC via whole-
exome sequencing: 660 lung adenocar-
cinoma (ADC) and 484 lung squamous
cell carcinoma (SCC) samples. They
found multiple mutated genes along
the RAS–RAF signaling pathway that
had not been associated with lung ADC,
including SOS1, RASA1, and VAV1.
Current targeted therapy research
in lung ADC is largely focused on
inhibiting receptor tyrosine kinases,
including EGFR, that activate RAS–
RAF signaling and are often mutated
in this disease. The discovery of previ-
ously unknown players along a main
driver pathway in lung ADC extends
the realm of possible therapeutic
targets, says senior author Matthew
Meyerson, MD, PhD, professor of
pathology at Dana-Farber Cancer
Institute in Boston, MA. It also under-
scores the importance of using large
sample sizes in genomic studies, he
Nikhil Wagle outlined the structure, recruit-ment strategy, and goals of the Metastatic Breast Cancer Project at the American Society of Clinical Oncology’s annual meeting in Chi-cago, IL, in June.
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NEWS IN BRIEF
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both are readily interpretable end
points in single-arm trials, especially
in a refractory patient population.”
Abemaciclib is also undergoing two
phase III assessments in breast cancer—
in combination with fulvestrant
(Faslodex; AstraZeneca) or with a non-
steroidal aromatase inhibitor. Because
it appears to cross the blood–brain
barrier, abemaciclib might be effective
in patients with central ner vous system
metastases, Dickler added. A phase
II evaluation is under way in patients
with breast cancer, non–small cell lung
cancer, or melanoma that has spread to
the brain. –Alissa Poh ■
Probing Biological Sex Differences in Cancer
An extensive analysis of data from
The Cancer Genome Atlas (TCGA) has
revealed considerable differences, at
the molecular level, between men and
women with certain cancers. The fi nd-
ings could help explain why the sexes
vary in terms of disease incidence, prog-
nosis, and response to therapy—well-
documented cancer disparities that have
not been systematically investigated
before (Cancer Cell 2016;29:711–22).
“We needed a large-scale data set
with suffi cient samples to enable rigor-
ous statistical control for confounding
factors such as race, age, and disease
stage, which wasn’t possible until
TCGA’s advent,” explains senior author
Han Liang, PhD, an associate professor
of bioinformatics and computational
biology at The University of Texas MD
Anderson Cancer Center in Houston.
Liang’s team focused on 13 cancers
in TCGA with molecular data on 30
or more samples from each sex. They
found that these cancers could be
separated into two categories. One,
the strong sex-effect group, comprised
eight cancers—including lung adeno-
carcinoma and head and neck squa-
mous cell carcinoma (HNSCC)—with
unequal male-to-female incidence and
mortality ratios. Five cancers, includ-
ing glioblastoma multiforme and acute
myeloid leukemia, were in the weak
sex-effect group, which had more bal-
anced incidence and mortality ratios.
The researchers uncovered a variety
of sex-biased somatic mutations and
copy-number changes in cancers in the
strong sex-effect group. For example,
men with lung adenocarcinoma had
a higher frequency of STK11 muta-
tions: This kinase activates the AMPK
pathway, and mutations in its gene are
thought to predict sensitivity to the
mitochondrial inhibitor phenformin,
at least in mouse models of lung
adenocarcinoma. Meanwhile, PIK3CA
was amplifi ed more often in women
with clear-cell renal cell carcinoma,
potentially infl uencing sensitivity to
mTOR inhibition; in the same cancer
in men, PDCD1, which encodes the
immune checkpoint protein PD-1, was
more frequently deleted.
The team then scrutinized 114
clinically actionable genes, including 86
whose alterations are targeted by FDA-
approved drugs. They reported that 53%
showed sex-biased differences in mRNA
and protein expression, among other
molecular signatures; these 60 genes
were almost all found in cancers of the
strong sex-effect group. For instance,
women with HNSCC had higher levels
of the SRC protein.
This fi nding could be relevant to the
failure of two clinical trials assessing
the SRC inhibitor dasatinib (Sprycel;
Bristol-Myers Squibb) for the disease,
Liang notes, because less than half
of the patients in each study were
women. Meanwhile, EGFR showed
female-biased mRNA expression in
lung adenocarcinoma, which he says is
consistent with the higher response rate
to EGFR inhibitors in women.
Biological sex is often not explicitly
considered when treating cancer, Liang
says. “Although this may be appropri-
ate for cancers in the weak sex-effect
group, the strong group merits special
consideration in terms of drug devel-
opment and clinical practice.”
The next steps for Liang’s team
include validating the sex-biased
and chemotherapy. The data were pre-
sented by Maura Dickler, MD, of the
breast medicine service at Memorial
Sloan Kettering Cancer Center in New
York, NY, during the American Society
of Clinical Oncology’s annual meeting
in Chicago, IL, June 3–7.
Cell-cycle control is frequently
disrupted in ER-positive breast cancer,
Dickler said, “making key regulators
such as CDK4 and CDK6 rational
targets for inhibition” with drugs like
abemaciclib, which halts the cell cycle
at the G1 phase.
A total of 132 patients with advanced
metastatic breast cancer were enrolled
on the MONARCH1 study. The objec-
tive response rate to abemaciclib was
19.7%, with a median duration of
8.6 months and 28.2% of responses
lasting at least 12 months. The
median progression-free survival was
6 months, and the median overall
survival was 17.7 months.
Abemaciclib was largely well toler-
ated, especially considering the patient
population, Dickler reported: Only
7.6% discontinued treatment due to
toxicity, and diarrhea, a main side
effect, was quickly resolved. Neutrope-
nia was less commonly seen than with
other therapies in this class, “prob-
ably because of the drug’s differential
impact on CDK6 inhibition,” she said,
noting that abemaciclib is 14 times
more potent against CDK4 than CDK6.
To date, palbociclib (Ibrance; Pfi zer)
is the sole CDK4/6 inhibitor to have
gained the FDA’s conditional approval
as first-line therapy, in combination
with letrozole, for postmenopausal
women with locally advanced or met-
astatic HER2-negative, ER-positive
breast cancer. Ribociclib (Novartis)
is in phase III development; mean-
while, abemaciclib was designated as a
Breakthrough Therapy by the FDA in
October 2015.
In a study of patients with heavily
pretreated, advanced metastatic breast
cancer, “any responses we see, we can
fairly well assume to be a consequence
of the drug,” said Tatiana Prowell,
MD, breast cancer scientifi c liaison
with the FDA’s Offi ce of Hematol-
ogy and Oncology Products. “That’s
why most successful Breakthrough
Therapy requests, including the one
for abemaciclib, have relied on objec-
tive and/or durable responses, because
AA
CR
These scans of a previously treated patient with advanced breast cancer and extensive liver metastases show tumor regression after two cycles of treatment with abemaciclib. (Originally published in Patnaik A, Rosen LS, Tolaney SM, Tolcher AW, Goldman JW, Gandhi L, et al. Cancer Discov 2016;6:740–53.)
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