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NonSmall Cell Lung Cancer, PD-L1, and the Pathologist

Keith M. Kerr, BSc, MB, ChB, FRCPath, FRCPE; Marianne C. Nicolson, MD, FRCP

 Context.Although most primary cancers of the lung

carry a heavy mutational load and will potentially present
many nonself antigens to the immune system, there are a
wide range of possible mechanisms for tumors to avoid socalled immune surveillance. One such mechanism is the
adoption of immune checkpoints to inhibit the host
immune response. Immune checkpoint inhibitors show
great promise in the treatment of advanced nonsmall cell
lung cancer.
Objective.To discuss the possibility of biomarker
selection of patients for these therapies. This is becoming
a much debated issue, and the immunohistochemical
detection of Programmed Death Ligand 1 (PD-L1), the
ligand for the inhibitory Programmed Death receptor 1
(PD-1) checkpoint, is one possible biomarker. Data so far
available show some conflicting results, but PD-L1
immunohistochemistry looks likely to be introduced into
clinical use for selecting patients for treatment with anti

PD-1 or antiPD-L1 therapies. Given that there are 4 such

drugs rapidly approaching regulatory approval, each with
its own independent PD-L1 immunohistochemistry biomarker test, both oncologists and pathologists face some
significant challenges.
Data Sources.Peer-reviewed literature and meeting
proceedings, especially during the last 12 months, were
Conclusions.The biology of PD-1/PD-L1 is complex,
the clinical data for these drugs show considerable
variation, the selection performance of the PD-L1 biomarker test is not perfect, and the existence of 4 drug/test
combinations adds significantly to the problems faced. This
article addresses some of the background to this therapeutic problem and discusses some of the issues ahead.
(Arch Pathol Lab Med. 2016;140:249254; doi: 10.5858/

L1 expressed in tumor samples has emerged as one such

possible biomarker, but its potential use poses many
questions and challenges for both oncologists and pathologists. Reviewed in this paper are PD-1 and PD-L1 as
immunomodulatory factors and as therapeutic targets, along
with the consideration of emerging PD-L1 companion
diagnostic biomarkers.

raditionally the treatment of advanced nonsmall cell

lung cancer (NSCLC) was limited to radiotherapy,
chemotherapy, or a combination of both, depending on
tumor stage and patient fitness.1,2 In recent years, molecular
targeted therapies have presented an alternative therapeutic
approach for patients whose tumors bear particular genetic
alterations.3 Early attempts at exploring immunotherapy in
lung cancers were disappointing, with poor responses to
BCG; cytokines, such as interferon; and antitumor vaccinations.46
Now, recognition of the relevance of the Programmed
Death receptor 1 (PD-1) and its ligand, Programmed Death
Ligand 1 (PD-L1), and the development of therapeutics
targeting PD-1 and PD-L1 has resulted in immunotherapy
being hailed as the third dimension in the treatment of
advanced-stage lung cancer.4,5 When a molecular target is
identified, there follows the search for a biomarker to
optimize the selection of patients most likely to benefit from
that therapy. The immunohistochemical assessment of PDAccepted for publication August 12, 2015.
From the Department of Pathology, Aberdeen University School of
Medicine (Dr Kerr), and the Department of Oncology (Dr Nicolson),
Aberdeen Royal Infirmary, Aberdeen, United Kingdom.
The authors have no relevant financial interest in the products or
companies described in this article.
Presented at the Biennial Meeting of the Pulmonary Pathology
Society; June 35, 2015; San Francisco, California.
Corresponding author: Keith M. Kerr, BSc, MB, ChB, FRCPath,
FRCPE, Department of Pathology, Aberdeen Royal Infirmary, Link
Building, Foresterhill, Aberdeen AB25 2ZD, United Kingdom (email:
Arch Pathol Lab MedVol 140, March 2016


Tumor cells (TCs) characteristically overexpress some
wild-type (WT) proteins and in addition express new,
nonself proteins and other macromolecules (neoantigens),
some of which are involved in driving the oncogenic
process. There is very limited evidence that viral infections
have a role in lung cancer development,7 so viral antigens
are unlikely to be significant in this disease, although the
more general process of posttranslational modification of
proteins is common in lung tumors. Tumor cells should
appear to the immune system as nonself and therefore
present a potential target for immune-directed therapy.
Tobacco carcinogenesis induces more mutations in lung
cancer than are found in most other solid tumors,8,9 but
historically lung cancer was considered to be nonimmunogenic. The reasoning was that this was due to loss of tumor
antigens, loss of sensitivity to complement, and lysis of T
and natural killer (NK) cells.7 More recent research has
revealed that lung tumors may develop mechanisms to
evade the attentions of the immune system in order to
develop and progress.4 Factors involved in this evasion
include loss of major histocompatibility complex (MHC)
antigen expression (perhaps due to gene loss or mutation),
PD-L1 Testing in NSCLCKerr & Nicolson 249

secretion of immunosuppressive cytokines, induction of

immunosuppressive T cells (Tregs), and, in the later stages
of disease, a more general failure of immune competence
due either to the disease itself or to treatment. Finally, a
complex series of immune checkpoint regulators appears to
be crucial in the fine-tuning of the immune response, and
this process may be co-opted by tumors to protect them
from immune attack.10 This latter mechanism will be
discussed later.
In the earliest stages of tumor evolution, NK cells
recognize a clone of malignant cells as foreign. The resulting
cell destruction leads to the release of tumor antigens, which
are taken up and processed by macrophages and dendritic
cells, probably within draining lymph nodes. Here cytokines
are produced and tumor antigens are presented in
conjunction with MHC class I molecules, leading to the
expansion of clones of antigen-specific T and B cells in the
process known as adaptive immunity. At the same time,
cytokine production promotes innate immune processes,
and these combined processes may lead to the complete
elimination of the malignant clone in addition to the
development of immunologic memory for those tumorassociated antigens. This is one possible outcome of
immune surveillance, or immune editing, where the
subclinical malignant clone is eliminated when that clone
is highly immunogenic and the immune system highly
competent.7,11,12 In some circumstances, such as where
tumor immunogenicity and/or host immunocompetence are
diminished, TCs may not be completely eliminated, but
their progression and growth are prevented by the immune
system, resulting in a state of equilibrium. Tumor cells may
remain viable but not clinically evident for many years,
without progression or elimination. This scenario is
consistent with clinical experience of very late recurrence
of malignant disease in some patients. A loss of immune
competence or a major change in the antigenicity of the
persistent cells may then lead to escape of the tumor from
immune surveillance, with resulting tumor progression.7,11
Changes in the tumor and its microenvironment that
suppress immunity and promote cell survival are associated
with progression. There is an increase in populations of
Tregs and myeloid-derived suppressor cells (MDSCs), and
the process is enhanced by proinflammatory, immunosuppressive cytokines, such as interleukin 10 (IL-10) and
transforming growth factor b (TGF-b; possibly produced
by Tregs, MDSCs, and TCs),6,13 with subsequent deterioration in T-cell function. It is believed that during this phase,
the TCs may also subvert the attentions of any competent T
cells by directly expressing suppressive immune checkpoints.10
A highly complex and diverse system of costimulatory and
inhibitory immune checkpoints exists, apparently functioning through binding of membrane-bound ligands and
corresponding receptors on the surface of a diverse range
of immune effector cells.10 At least 13 ligand-receptor pairs
are recognized that could potentially interact in conjunction
with the binding of MHC molecules bound to antigen with
the T-cell receptor. These molecular interactions either
activate or inhibit the immune response, and they provide a
mechanism whereby the intensity of the immune response
is controlled. It is crucial that there be modulation of the
duration and intensity of the physiological immune re250 Arch Pathol Lab MedVol 140, March 2016

sponse to minimize collateral tissue damage. These mechanisms are also important in creating immune tolerance and
the prevention of autoimmune disease. Their importance in
inhibiting an effective immune response to tumor antigen
makes them attractive targets for therapeutic intervention.
In terms of malignant disease, one of the first inhibitory
immune checkpoints to be targeted was cytotoxic Tlymphocyteassociated protein 4 (CTLA-4), an immune
checkpoint receptor that is exclusively expressed on T cells,
with CD80 and CD86 as ligands.10 Recently, however, much
attention has been paid to PD-1 and its ligand PD-L1 and
how this interaction might be blocked in NSCLC by
immunomodulatory therapies, such as therapeutic monoclonal antibodies specific for either PD-1 or PD-L1.
PD-1 is expressed by T cells, including Tregs, but also by
NK cells and some B cells. It is involved in the later stages of
the immune response, regulating the activation of T cells in
peripheral tissues. PD-1 has two ligands, PD-L1 (also
known as B7-H1 or CD274) and PD-L2 (B7-DC or CD273).
These ligands are expressed on a wide range of immune
effector cells, antigen-presenting cells, and TCs. The
expression of PD-L1 by TCs may be a key mechanism by
which they inhibit immune activity. This expression may be
constitutive, related to abnormal TC gene expression. In
some tumors loss of phosphatase and tensin homolog
(PTEN) expression and upregulation of the protein kinase
Bphosphatidylinositol-3-kinase (AKT-PI3K) pathways has
been implicated, whereas signal transducer and activator of
transcription 3 (STAT3) signaling may be involved in
anaplastic lymphoma kinase (ALK) rearranged lung cancers.10 PD-L1 gene amplification is also seen in some tumors
and is associated with high levels of PD-L1 protein in TCs.14
PD-L1 expression may also be induced by interferon c,
which is produced largely by T-helper 1 cells as part of a
host inflammatory response; this process is referred to as
adaptive immune resistance. PD-L1 expression is heterogeneous within tumors and may be seen more frequently in
areas of tumor with higher levels of tumor-infiltrating
lymphocytes.10 However, this is at odds with an observation
recently reported where, using the SP142 clone for PD-L1
immunohistochemistry (IHC), cancers expressing high
levels of PD-L1 in TCs lacked high numbers of tumorinfiltrating lymphocytes, and those tumor-infiltrating lymphocytes present lacked much PD-L1 expression.14 The
same study also reported that tumors with high levels of
PD-L1positive tumor-infiltrating lymphocytes tended to be
rich in CD8 cells, whereas those with high PD-L1
expression in TCs tended to have a sclerotic stroma and
few CD8 cells. The exact implications of these observed
interrelationships are not clear, and much more work is
required to clarify understanding of such complex biology.
The fact that PD-L1 is inducible by inflammatory cytokines
released into the TC microenvironment is important when
considering the findings of PD-L1 expression studies in
samples from patients with NSCLC (see below). Studies of
PD-L1 expression in lung cancer report a prevalence of 13%
to 70% positivity for this biomarker, partly dependent on
how expression is tested for and defined.15 There is also
evidence that higher expression of PD-L1 in surgically
resected NSCLC is a poor prognostic factor, implicating
down-regulation of the host immune response to the tumor
as a means of ensuring TC survival.16,17 Conversely, evidence
PD-L1 Testing in NSCLCKerr & Nicolson


There is in vitro evidence that although some chemotherapeutic agents may reduce PD-L1 expression in cell lines,
others, such as paclitaxel and etoposide, can increase
expression.13 It is unknown whether these effects are seen
in vivo, but such changes could be confounded by the
potential for the inflammatory responseinduced by the cell
death resulting from chemotherapyto induce PD-L1
expression as well as other elements of the immune
response. There are anecdotal reports that chemotherapy
can induce PD-L1 expression, so a tumor that tests as PD-L1
negative in the diagnostic biopsy could be PD-L1 positive
after chemotherapy, or at disease progression/relapse. More
studies are required to improve our understanding of this

treatment of patients whose NSCLC showed less than

50% of TCs expressing PD-L1 demonstrated a median
survival of about 9 months, whereas for those with tumors
scoring 50% or more TCs as PD-L1 positive, median
survival was not reached with 26 months of follow-up.25
Considering histology, in patients with nonsquamous cell
carcinoma treated with nivolumab or docetaxel, both PFS
and OS were significantly better in the nivolumab-treated
groups when PD-L1 expression was deemed positive, and
hazard ratios improved from 0.59 to 0.40 for OS as PD-L1
expression levels increased.29 A similar outcome and trend
of improved hazard ratio for OS with increasing PD-L1
expression is also reported in NSCLC treated with
atezolizumab.30 This difference in survival dependent on
PD-L1 expression was not found with nivolumab in patients
with squamous cell carcinoma where the improvements in
PFS and OS were independent of the level of PD-L1
biomarker expression.27 This latter observation has
strengthened the conviction among some oncologists that
the case for patient selection according to biomarker status
may be premature.
Each of the 4 distinct PD-1targeting or PD-L1targeting
drugs in development mentioned in this review has been
developed with its own biomarker test for PD-L1 IHC.
Should these drugs enter clinical use with selection for
treatment based on the PD-L1 IHC status of the tumor, then
some significant challenges lie ahead.


Early success with therapeutic antiPD-1 monoclonal
antibody checkpoint inhibitors (immune checkpoint inhibitors [ICIs]) tested in a number of tumor types5,6,22,23 has
been followed by a large number of studies in NSCLC, using
either PD-1 (nivolumab, pembrolizumab) or PD-L1 (atezolizumab, MEDI-4736 [durvalumab]). Phase 1 data showed a
median overall survival (OS) of 9.9 months in heavily
pretreated NSCLC patients treated with nivolumab,24 and 12
months for pembrolizumab, where about 20% of patients
were chemonaive.25 Most studies have recruited heavily
pretreated patients with advanced NSCLC treated in second
or later lines of therapy, comparing checkpoint inhibitors
against the standard of care regimen, docetaxel delivered as
a single agent. Standard Response Evaluation Criteria in
Solid Tumors (RECIST) criteria for response evaluation are
not best suited to capture the responses to immunotherapy
where it is recognized that tumor growth may be seen before
shrinkage occurs. However, there are consistent reports of
objective response rates around 20% to 25%, and in some
cases up to 80%, in NSCLC.15,24,26 Durable progression-free
survival (PFS) and OS are increasingly recognized in patients
with advanced disease.24,25,27
A consistent finding in many of the early studies has been
higher response rates to checkpoint inhibitors in tumors
found to express higher levels of PD-L1 measured by IHC,
when compared with those that were either negative or
expressed PD-L1 at lower levels.15,28 Although there is
variability between trials in the definition of PD-L1
negative, the response rates reported in such patient
cohorts are frequently equivalent to or higher than those
observed for docetaxel. As discussed above, the biomarker
data being predicated on the original chemonaive biopsy
has led to concerns about the actual PD-L1 status of the
tumors treated in second-line therapy. Pembrolizumab


The therapeutic successes seen to date with ICI therapy in
NSCLC, coupled with the likely requirement for PD-L1 IHC
testing to ensure optimal patient selection, will demand
further biomarker assessments by pathologists. Such tests
will be carried out on the same small diagnostic samples
that are frequently barely adequate to provide the initial
diagnosis and mutation testing. If ICI therapy is to be
prescribed as second-line therapy, questions arise around
the timing of the test, whether as part of the initial
diagnostic workup or indicated only at the point when ICI
therapy is being considered. PD-L1 expression testing
performed on archived tissue at any time point after the
initial diagnostic cycle may be challenging because of
insufficient residual material being available. It is presently
unclear whether there is a need for rebiopsy of recurrent
disease to provide a more contemporaneous biomarker test
result. Considering the potential for there to be several
licensed ICI drugs are available, each with its own
biomarker test, how will the pathologist know which test
to perform? Uncertainty will have an impact on the ability of
the pathologist to practice reflex testing for PD-L1, and
result in the ability to provide only a bespoke service at the
request of the oncologist.
The intensely competitive nature of drug development in
a challenging commercial environment, coupled with the
need to meet regulatory requirements, undoubtedly drove
the evolution of each of the 4 ICI drugs discussed here in
conjunction with its specific biomarker test, which depends
on IHC. Although it is an exceptionally useful diagnostic
technique that is relatively easy to perform, IHC interpretation is complicated by the fact that different clones of
monoclonal antibodies raised against the same protein will
be specific for different protein epitopes. The subsequent
visualization of the bound primary antibody on the tissue

of an active immune response in the same clinical setting

confers better postoperative survival.1821
PD-1 activation by ligand binding produces a number of
intracellular effects that result in T-cell inactivity and
reduced proliferation.13 This regulation may be mediated
by SH2 domain-containing protein-tyrosine phosphatase
(SHP2) signaling to produce inhibition of V-Ki-ras2 rat
sarcoma viral oncogene (KRAS) and downstream targets
extracellular signal-regulated kinases 1 and 2 (ERK1 and
ERK2). PI3K and AKT are also inhibited.

Arch Pathol Lab MedVol 140, March 2016

PD-L1 Testing in NSCLCKerr & Nicolson 251

section depends on the detection system used, and here

again, there is scope for variation in reports. Consequently,
one PD-L1 IHC test may not necessarily perform in the
same way as any other.
Using the example of nivolumab, biomarker studies
conducted in trials of this agent used the antiPD-L1 IHC
antibody clone 28-8 (Dako, Glostrup, Denmark). In these
studies, TC staining for PD-L1 was assessed using different
thresholds (1%, 5%, and 10%) to define positive
staining.27 Alternatively, with pembrolizumab the biomarker
test uses a different antiPD-L1 Dako clone, 22C3. In this
test, the trials considered two positive thresholds of TC
staining (1% and 50%), and the published data support
the use of a threshold of 50% or greater for clinical use.25
The two other ICI drugs that are most advanced in
development are MEDI-4736 (durvalumab) and atezolizumab, and each has its companion diagnostic test based
around different clones of antiPD-L1Ventana SP263 and
SP142 (Tucson, Arizona), respectively. The former test for
MEDI-4736 (durvalumab) assesses TC staining, and the
positive threshold is 25% or greater.31 The companion test
for atezolizumab, using the SP142 clone, is more detailed
because an assessment of both TC and/or tumor-associated
immune cells (ICs) is required. For TCs, 4 different grades of
staining have been considered in clinical trials (TC0-3),
defined around cut points of 1%, 5%, and 50% TC staining.
For ICs, it is the area of tumor infiltrated by PD-L1
expressing ICs, expressed as a percentage with cutoffs at 1%,
5%, and 10%, that is used to define IC0-3.30
Although including IC in the scoring algorithm may
appear to increase complexity, it is intuitive to consider the
IC infiltrate in such an assessment and, depending on which
level of positive staining might be considered relevant for
therapy selection (IC1-3), IC positivity alone could account
for 6% to 30% of patients treated, with response rates
similar to those predicted by TC staining alone.30 As
mentioned above, there is almost no overlap between cases
scoring TC3 and IC3.14 Interestingly, expression of 22C3 on
ICs did not add useful data regarding patient selection for
pembrolizumab.25 With the possible exception of this latter
drug/test combination, it is not clear at the time of writing
which thresholds (if any) will be used to select patient
selection for treatment with the other ICI currently available.
Although the testing situation for ICI use appears complex
and currently poorly defined, it is worth remembering that
pathology already delivers successfully on complex diagnostic and predictive IHC testing; with education and
experience, excellent accuracy and consistency can be
achieved.32,33 Immunohistochemistry testing is also relatively inexpensive, and results can be available rapidly. If these
test results are a requirement prior to prescription of ICIs,
organizations that ensure external quality assurance in
biomarker testing will clearly be involved to minimize error.
Inevitably debate will ensue regarding who should perform
and read these tests. Experience with human epidermal
growth factor receptor 2 (HER2) testing in breast cancer in
the United Kingdom indicates that improved test results are
realized through some degree of centralization coupled with
explicit training and higher caseloads.33 Although it is
possible to produce very reliable and accurate home brew
laboratory-developed tests, not every laboratory has the
time or experience to validate laboratory-developed tests.
Additionally, for IHC tests, differential epitope recognition
and variation in detection systems used can lead to true
biologic variability in IHC outcomes for what is considered
252 Arch Pathol Lab MedVol 140, March 2016

the same test. Consideration must also be given to the

potential effect on the PD-L1 antigen epitopes of preanalytical issues, for example, epitope stability in tissue blocks
and cut sections, and the possibly deleterious effects of
formalin fixation or other tissue-processing chemistry.34
Companion diagnostic tests are more expensive, reflecting
in part the costs of developing and validating them, and
although the results will still be affected by preanalytic
issues, they have the potential to produce consistent and
accurate staining, provided they are used as recommended.
Any variation from methods reported in the peer-reviewed,
published clinical trials risks a reduction in reliability of
clinical results. Although more expensive than routine
diagnostic IHC testing, predictive companion diagnostics
are still much cheaper than the drugs with which they are
allied, and relatively cheap testing can be viewed as an
efficient investment to prevent the use of expensive drugs in
patients who will not benefit from the treatment. This
complex argument certainly pertains in the context of ICI
therapy, but further debate is beyond the scope of this
In clinical trials, eligibility requirements virtually always
mandate a tissue biopsy for biomarker testing. There are
many likely reasons for this, but the end result is that
biomarker tests proven in trials are rarely validated for
cytology samples, which in routine practice provide the
diagnosis in more than half of the patients given a diagnosis
of lung cancer. Cytology cell blocks and cytospin preparations can be excellent materials for many biomarker tests,
including IHC. For PD-L1 testing in TCs it will be possible
to carry out IHC on these preparations, but careful
validation will be required to ensure acceptable test
performance at a technical level. It is difficult to think of a
good reason why the test should not have the same
predictive power in cytology and biopsy specimens. Some
tests, for example, 22C3, mandate an IHC score on at least
100 TCs,25 and a significant number of both cytology cell
blocks and biopsy samples will fall short of that figure. A
greater challenge lies ahead with regard to any need to
assess PD-L1 expression in tumor-infiltrating ICs.30 In a
cytology sample, the relationship of ICs to TCs is never
clear. The ICs could be bystanders, present for a reason
unrelated to the tumor, or a normal part of the structure
from which the sample was takenespecially because a
significant proportion of lung cancer cytology samples
derive from lymph node aspirates. Furthermore, if the IC
score is assessed as a percentage area of tumor infiltrated by
PD-L1positive ICs, rather than a percentage of IC stained,
then cytology samples are completely ruled out from being
suitable for this assessment.
PD-L1 expression in TCs is variable and dynamic because
it is a pathophysiologically inducible factor, and it will be a
continuous variable from zero through low to high levels.
When an IHC test is scored, the degree of staining (the
percentage of positive cells) places the case somewhere in
the range of this continuous variable. The advent of a cutoff
or threshold to define a positive/negative test result is
artificial. Such a definition creates the illusion of a binary
system akin to, for example, the presence or absence of an
epidermal growth factor receptor gene (EGFR) mutation.
Several of the clinical studies mentioned here report
PD-L1 Testing in NSCLCKerr & Nicolson

improving hazard ratios for OS and PFS with increasing

levels of PD-L1 staining, indicative of a dose-response
relationship between PD-L1 expression and drug efficacy.25,29,30 If we consider the theoretical example of a 50%
threshold, this implies a lower chance of response if the case
scores anywhere below the threshold, and vice versa above
it. Clearly the continuously variable nature of the test
parameter means that there will be very little difference in
probability of outcome for a patient who scores just below
the threshold compared with one just above it. Conversely,
a patient with expression just above the threshold will have
less probability of a good outcome compared with the
patient with a maximum score, even although both score
positive. Therefore, the expectations for a PD-L1 test need
to be tempered, and understood to be less reliably predictive
than, for example, the EGFR mutation test.
It would be ideal for all concerned if there were agreement
on a single qualifying test, but, for all of the reasons
mentioned above, this may be impossible to achieve.
Because of even subtle differences in chemistry, these IHC
tests could behave differently in the same tissue. Even if
there are no major differences in staining, the definitions of
a positive PD-L1 test result, predictive of response, vary
considerably between tests. There are no studies currently in
the public domain to confirm or refute this hypothesis, but
the International Association for the Study of Lung Cancer
is working with various stakeholders in an attempt to assess
the technical equivalence of the available tests. Notwithstanding the differences in scoring algorithms likely to be
applied to each companion diagnostic, it will be very difficult
to demonstrate with any scientific rigor that there is
predictive equivalence, in terms of patient outcome, should
a test other than the trial-proven approach be used for
selecting patients to receive a particular treatment. Without
this evidence, any deviation from practice validated in the
trials could be disadvantageous to patients.
The results for immune checkpoint inhibitor therapy in
patients with lung cancer are encouraging. Current data
suggest that PD-1 and its ligand PD-L1 are promising
targets, and monoclonal therapeutic antibodies have shown
excellent results in terms of RR, PFS, and OS, primarily in
second-line therapy for patients with advanced NSCLC
where the current standard of care is suboptimal and
potentially toxic. Current data show that patient outcomes
are generally better with these therapies when there is an
increase in PD-L1 expression as measured by IHC.
However, the place of this biomarker in treatment decisions
is still not absolutely clear, because in some studies
responses are seen in biomarker-negative patients. The
enormous potential costs of these therapies coupled with
high clinician and patient expectation may mandate the
identification of a smaller patient group in whom clinical
benefit is most likely to be seen.
PD-L1 IHC is the best currently available biomarker,
although it is not optimal. Given the nature of this test and
the biology behind it, appropriate expectations are required
to temper criticism. Other potential biomarkers include
smoking history, tumor mutational load, the presence and
type of tumor-infiltrating immune cells, immune response
Arch Pathol Lab MedVol 140, March 2016

gene signatures, and the influence of other immune

checkpoint regulatory factors. The possibility of a choice of
4 different drugs and 4 different approaches to PD-L1 IHC
testing would bring significant challenges for both oncologists and pathologists. None of these issues are insurmountable, however, because there is ample evidence that
pathologists can deliver timely and reliable test results,
provided the appropriate investments are made in personnel, education, and equipment. Ever closer cooperation and
dialogue between oncology and pathology specialists will be
necessary to ensure that each patient receives the most
appropriate therapy. We anticipate many further developments in this rapidly evolving therapeutic field.
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CAP16 Abstract Program Submission Dates

Abstract and case study submissions to the College of American Pathologists (CAP) 2016 Abstract
Program will be accepted beginning on Friday, January 8 through 5 p.m. Central time Friday, March
11, 2016.
Accepted submissions will appear on the Archives of Pathology & Laboratory Medicine Web site as
a Web-only supplement to the September 2016 issue. The CAP16 meeting will be held from
September 25 to 28 in Las Vegas, Nevada.
Visit the CAP16 Web site ( for additional abstract program information as it
becomes available.

254 Arch Pathol Lab MedVol 140, March 2016

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