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

810 | CANCER DISCOVERY�AUGUST 2016 www.aacrjournals.org

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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