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Stage trumps
biology for most
small triple-
negative breast
cancers
BY BRUCE JANCIN
Frontline Medical News
P
atients with stage T1a or T1b triple-
negative breast cancer have an
excellent prognosis even without
chemotherapy, according to Dr Eric P.
Winer.
“There’s a perception on the part of
many patients and physicians that all
triple-negative breast cancer is bad,
and that it’s destined to threaten and
ultimately take a woman’s life. But even
in an era where biology is king, stage
still matters,” he observed at the San
Antonio Breast Cancer Symposium.
He was a coinvestigator in a recent
prospective cohort study which included
4113 women with stage T1a or 1b breast
cancer – that is, a tumour size no greater
than 10 mm in its greatest dimension –
without regional lymph node metastases
or evidence of distant metastases. The
patients, drawn from the National Com-
prehensive Cancer Network database,
were treated in accord with institutional
practice and followed for a median of
5.5 years.
Slightly over half of those in the sub-
set with triple-negative breast cancer
(TNBC) got chemotherapy. Those who
received chemotherapy for T1a TNBC as
defined by a tumour size not greater than
5 mm had a 5-year distant relapse-free
survival (DRFS) of 100%, but the rate
was still close to 95% in those not treated
with chemotherapy. Outcomes were also
quite favourable for patients with T1b
TNBC who didn’t receive chemotherapy
(
J Clin Oncol
2014;32:2142–50), said
Dr Winer, chief of the division of wom-
en’s cancers at the Dana-Farber Cancer
Institute and professor of medicine at
Harvard Medical School, Boston.
He noted that the findings in this
study echo those of an earlier study
by investigators at University of Texas
M.D. Anderson Cancer Centre, Hou-
ston, who reported a 5-year DRFS rate
of 96% in 125 patients with T1a or 1b,
lymph node-negative TNBC untreated
with chemotherapy (
J Clin Oncol
2009;27:5700–6).
Dr Winer said that while the consen-
sus among most experts is that standard
adjuvant chemotherapy regimens for
patients with stage 2 or 3 TNBC in-
clude both anthracyclines and taxanes,
his own view is that for patients with
stage 1 TNBC “if you’re going to pursue
chemotherapy, then treatment with a
somewhat less toxic, shorter regimen
would seem to be more appropriate.”
Pembrolizumab shows promise in PD-L1–
positive breast cancer
BY SUSAN LONDON
Frontline Medical News
T
he immune checkpoint inhibitor pem-
brolizumab appears safe and modestly
active in women with oestrogen receptor
(ER)-positive, HER2-negative advanced breast
cancer that expresses programmed death-ligand
1 (PD-L1), according to preliminary results of
a phase Ib trial presented at the San Antonio
Breast Cancer Symposium.
Nineteen percent of women screened for
the trial, KEYNOTE-028, had archival or fresh
tumours from nonirradiated sites that tested
positive for this ligand by immunohistochem-
istry, reported lead investigator Dr Hope S.
Rugo, clinical professor in the department of
medicine (haematology/oncology) and director
of the breast oncology clinical trials program
at the University of California, San Francisco.
A total of 25 of these women received at least
one dose of pembrolizumab, an antibody to the
PD-1 (programmed death-1) cell surface recep-
tor that blocks interaction of the receptor with
its ligands, thereby preventing the inactivation
of T cells. (The antibody is currently approved in
Australia for the treatment of melanoma.)
With a median duration of follow-up of 7.3
months, the overall response rate as assessed
by investigators using RECIST criteria was
12%, and the clinical benefit rate was 20%,
Dr Rugo reported. Responses were durable,
lasting anywhere from about 9 weeks to more
than 44 weeks.
The rate of grade 3 or 4 adverse events was
16%. Only a single patient had to have interrup-
tion of pembrolizumab because of the develop-
ment of an immune adverse event.
“Based on these data, we believe that further
investigation of immune therapies in ER-posi-
tive, HER2-negative breast cancer, particularly
using combination therapies that can expand the
T-cell compartment, are warranted,” Dr Rugo
maintained.
She noted that the trial’s findings differ
somewhat from those of a similar trial testing
avelumab, an investigational antibody against
the PD-L1 ligand itself, that was presented
at the symposium (abstract S1-04). That trial
found a much higher PD-L1 positivity rate in
screened women, 55%, and a much lower overall
response rate, 3%.
These differences may have been
due to use of different immuno-
histochemical assays for PD-L1,
lack of data for some patients in
the other trial, and/or differences
in the target of the agent used (PD-
1 vs PD-L1), she speculated. “It’s
clear that as we move forward in
this field of immunotherapy, which
we are all very excited about, that
standardization of assays assessing
PD-L1 positivity are going to be
critical,” she concluded.
“After how many studies will we
be convinced [given] the discord-
ance between different antibodies
[and] scoring mechanisms, and
the very, very weak enrichment
in responders, that PD-L1 stain-
ing is not an adequate biomarker
for these agents?” asked session
attendee Justin Balko, PharmD,
PhD, of Vanderbilt University,
Nashville, Tennesse.
“I think that we are going to
need a consortium as well as
development of guidelines for
the best methods to test PD-L1 expression,
whether that’s an immunohistochemical test,
looking at mRNA, or looking at pathway activa-
tion,” Dr Rugo replied. “Whether we need to
include for example TILs [tumour-infiltrating
lymphocytes] in evaluation or quantification of
lymphocytes, which may or may not be practical,
remains to be seen,” she said, adding that this
research will require a collaborative effort.
Another attendee speculated that the dispa-
rate findings for the two trials may have been
due to reliance on RECIST criteria in the KEY-
NOTE-028 trial. “I wonder if you had the op-
portunity to explore any of the immune-related
response criteria that have been evaluated in
other settings like melanoma,” she said.
“As a breast cancer field in immunotherapy,
we are kind of behind everybody else, and we
are just now starting to use immune RECIST
as part of our assessments for the studies going
on now prospectively in breast cancer,” Dr Rugo
replied. “ So no, we didn’t use immune RECIST.
But it’s an interesting area to go back and look
at, to see whether or not we can reclassify any
of the responses.”
Giving some background to the research, she
noted that PD-L1 expression has been inversely
correlated with ER expression. A previous trial
found an overall response rate of about 19% in
triple-negative breast cancer (SABCS 2014,
abstract S1-09).
For KEYNOTE-028, patients were screened
for PD-L1 positivity, even though pembrolizum-
ab targets PD-1, because there is much greater
variability in ligand levels than in receptor levels
when it comes to determining T cell inactiva-
tion, Dr Rugo explained.
Fully 80% of the 25 women treated had re-
ceived three or more prior lines of therapy for
their advanced disease. They were give pem-
brolizumab every 2 weeks with assessments
every 8 weeks initially.
The grade 3 or 4 adverse events observed
were cases of autoimmune hepatitis, increased
gamma-glutamyl transferase levels, muscle
weakness, nausea, and septic shock. However,
there were no treatment-related deaths.
In patients who developed any-grade immune-
related adverse events of interest, just one – a
patient with autoimmune hepatitis – had to have
treatment interruption.
All of the responses observed were partial
responses. The median time to response was
8 weeks, and the median duration of response
was not reached, with a range from about 9 to
44 weeks. The three patients with a response
had been in the study for at least 26 weeks as
of the data cutoff for analysis.
“Cost is an issue with these drugs,” said at-
tendee Dr Mark Graham II, an oncologist with
Waverly Haematology Oncology, Cary, North
Carolina. “I’m particularly interested in your
nonresponders and the fact that we can see
pseudoprogression with these drugs. So for the
eventual nonresponders, …what is the likely
number of cycles that will be necessary to con-
clude that a patient is not an initial responder?”
That number is difficult to accurately pin
down, as patients in the trial were taken off the
agent as early as 8 weeks along if they had any
evidence of progression, Dr Rugo said. “I really
don’t think we know the answer yet, but if you
went out to 16 weeks, all the patients that we
saw who were going to respond had responded
by 16 weeks.”
An accurate answer will likely require future
studies, she added. “I think it’s most complicated
in triple-negative disease, where a small phase
Ib trial showed a very long median time to re-
sponse. So this is a good question and it remains
to be answered.”
If sufficient tissue is available, the investigators
plan to look for other biomarkers of pembroli-
zumab benefit, such as proliferation markers and
intrinsic subtype, according to Dr Rugo. “Prob-
ably those more in-depth investigations are going
to occur with future studies, just because of the
need to acquire enough tissue to do them. This
trial was exploratory,” she said.
Dr Rugo disclosed that her institution receives
research funding from Merck & Co. – the trial
sponsor – and Genentech.
There’s a perception on the
part of many patients and
physicians that all triple-negative
breast cancer is bad, and that
it’s destined to threaten and
ultimately take a woman’s life.
But even in an era where biology
is king, stage still matters.
Based on these data, we believe
that further investigation of immune
therapies in ER-positive, HER2-
negative breast cancer, particularly
using combination therapies that
can expand the T-cell compartment,
are warranted.
© SABCS/Todd Buchanan 2015
Vol. 9 • No. 1 • 2016 •
H
aematology
& O
ncology
N
ews
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San Antonio Breast Cancer Symposium 2015