diagnostics are biomarker tools (usually quantification of gene expression,
protein levels and qualitative detection of polymorphisms associated with a
disease) to individualize and guide a therapy1. They are often
applied in order to monitor a therapy, to evaluate the risk/benefit ratio for a
patient and to determine if a patient is likely to benefit from a treatment or
is at high risk of getting side effects9.

diagnostics are often combined with diagnostic methodologies, which not only
indicate the target, but also the off-target effects of a drug, predicting
adverse effects caused by the drug9.

They are
often developed either through retrospective data of clinical studies3
or simultaneously with drugs (either chemotherapeutics or monoclonal
antibodies), the efficacy and safety of which they are designed to predict for
each individual patient. Companion diagnostics as assays are clinically
validated during late clinical phases of the corresponsive drug, where they divide
patients into groups according to their variability in response to the drug, in
order to become regulatory approved at the same time with the drug and monitor
the therapy.1

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A companion
diagnostic should refer to a particular therapeutic product in its label and
this therapeutic product should require undergoing the companion diagnostic
before being prescribed.2

In terms of device, drug
response prediction and therapy monitoring there are several types of companion
diagnostics: in vitro assays in biopsy materials (immunohistochemistry,
fluorescence in situ hybridization) or in whole blood (genetic tests) or imaging
tools, screening assays that detect genetic polymorphisms, theranostics that
predict patient’s phenotype and his/her response to a treatment, prognosis and
recurrence tests that predict the progression of a disease and monitoring
assays that determine ongoing efficacy and the suitable dose of a medicine for
a patient.2

Main part

Companion diagnostic for Herceptin(trastuzumab)

companion diagnostics were developed to guide the use of oncology drugs,
although rapidly they found application in various therapeutic areas. 2

The first companion
diagnostic to be developed was Herceptest. HER2 (human epidermal growth factor
receptor 2) is a tyrosine kinase receptor, encoded by the ERBB2 gene, found overexpressed in breast cancer.

Herceptest includes
an immunohistochemistry assay, estimating the HER2 expression, in formalin-fixed,
paraffin-embedded (FFPE) breast cancer tissue specimens and FFPE specimens from
patients with adenocarcinoma of the stomach and a fluorescence in situ
hybridization (FISH) assay to quantitatively evaluate determine ERBB2 gene amplification in the same

is used to and categorize breast cancer patients according to risk for
recurrence and to determine breast cancer patients who are expected to respond to
trastuzumab treatment based on the score that is gained in the IHC and FISH
assays and that indicates the intensity of staining in accordance with
percentage of stained tumor cells)11,12.

 Companion diagnostic for Pembrolizumab (Keytruda)

death receptor-1 (PD-1) is expressed on the surface of T-cells and when
interacts with PD-1 ligand-1 being overexpressed in tumor cells of5 patients
non–small cell lung cancer (NSCLC), the tumor cells evade immune attack and
survive. Pembrolizumab is a monoclonal antibody that targets PD-1 andinhibits
binding of PD-1 with its ligand, exerting this way an antitumor effect.5

IHC 22C3
pharmDx test, (Dako) is an approved companion diagnostic in advanced NSCLC, which
is used to predict which patients are most likely to respond to treatment with
pembrolizumab. More precisely, it is a PD-L1 immunohistochemical assay which is
applied in formalin-fixed, paraffin-embedded (FFPE) tumor-tissue samples
with at least 100 viable tumor cells of patients with NSCLC and uses the 22C3
anti–PD-L1 mouse monoclonal antibody and hematoxylin as a staining agent. In
case a patient with NSCLC undergoes this test and demonstrates a minimum TPS
score of 50%, which means that the membrane of 50% or more of viable tumor
cells is partially or completely stained at any intensity, this patient is eligible
to treatment with pembrolizumab.

As with most companion diagnostics, however, there is
doubt regarding the prognostic value of this companion diagnostic, as it can be
affected by the presence of inflammatory cells in the sample, the heterogeneous
expression of PD-L1 in tumor cells and the immune alteration of tumor cells, a
tumor sampling error and the tumor type.5

Companion diagnostic for PARP inhibitors

Homologous recombination (HR) consists of pathways
that contribute in the repair of DNA double-stranded breaks and interstrand
crosslinks6. BRCA2 and BRCA1 are known tumor suppressor genes
that involve not only in DNA replication and transcription regulation, but also
in HR repair8. Mutations in BRCA2 and BRCA1 genes are considered to be implicated in hereditary breast
and ovarian cancer6.
Epithelial Ovarian Cancer (EOC) tumors with Homologous Recombination Deficiency
(HRD) exhibit sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors in
clinical practice7, as PARP
inhibition in combination with Homologous Recombination Deficiency in HRD cells,
such as BRCA mutated cells, leads to DNA
damage and synthetic lethality (tumor cell death by accumulation of non-lethal DNA
repair failures)8. Next generation sequencing (NGS) is applied in
order to investigate genomic alterations in EOC which are linked to HRD and to
predict response to PARP inhibition, identifying patients for precision

BRACAnalysis CDx™ is an in vitro diagnostic device using whole blood
sample from a patient, approved by FDA. It consists of two in vitro assays that
detect and classify germline variants in five categories: Polymerase chain
reaction (PCR) or Sanger sequencing to detect small inser­tions and deletions (?5
basepairs) and single nucleotide polymorphisms (SNPs) in exons and exon/intron
junctions of BRCA1/2, and multiplex
PCR to detect large rearrangements in BRCA1 and BRCA2. Therefore, this companion
diagnostic contributes in identification of EOC patients with detrimental BRCA1/2 polymorphisms and allows for
prediction of the patients who are most likely to benefit from olaparib (PARP
inhibitor) 8.

regarding the application of this assay is that it is limited in detection only
of known genetic polymorphisms. Another limitation is that this technique is
unable to distinguish gene dupli­cation from triplication and sometimes could
provide false negative results due to uneven allele amplification (in case of
presence of SNP at a primer site) 8.

Implications for clinical care -Impact of companion
diagnostics on efficacy-safety of targeted anticancer-therapy

According to
results coming from analysis that consisted of randomized clinical trials
(RCTs) estimating efficacy and toxicity of 28 targeted anticancer-agents (approved
by the US Food and Drug Administration since year 2000) with or without
utilization of a companion diagnostic, it was found that companion diagnostics
were linked with higher tolerability and improved safety.3

Implications for clinical care – Limitations

in application of companion diagnostics derive either from the molecular assay9
or improper handlings independent of the diagnostic test such as false
isolation of tumor sample5.

diagnostics assess the presence of a biomarker qualitaitively and quantitatively
(gene expression or gene polymporphism), but provide little information about
the localization of a biomarker. Thus, diagnostic imaging (such as magnetic
resonance imaging-MRI or PET) is necessary for effective application of a
companion diagnostic test, especially in monitoring cancer patients. Furthermore,
companion diagnostics evaluate only one biomarker, while resistance to a drug
in some cases can be predicted by taking into account multiple biomarkers (ie. EGFR
expression and KRAS mutations predict both eligibility to EGFR inhibitors). This
fact in combination with possible low sensitivity of some companion diagnostics
set limitations in their use. These limitations require additional data, gained
from other assays (such as Next Generation Sequencing or imaging methods) in
order to be overcome and when they get ignored, misleading inaccurate results

Indeed, false negative results were
recorded regarding identification of EGFR mutations in patients with non small
lung cancer (NSLC), due to tumor sampling error or failure to report and
identify limitations of testing assays, resulting in false ineligibility of
these patients to be enrolled in phases 2 and 3 of a novel targeted therapy10.


Companion diagnostics seem to be an
important tool regarding drug development and precision medicine in clinical
practice. It seems that an increase in the number of companion diagnostics, as
expected in the near future in the field of oncology, would lead to a more
cost-effective pharmacotherapy benefiting patients and healthcare system1.
However, there are limitations in use of companion diagnostics, which may
result in misleading results. Therefore, in order for the companion diagnostics
to provide accurate and true results, the awareness of the limitations of the
companion diagnostics assays should be raised. Moreover, a combination of them
with an alternative procedure (NGS or an imaging method) suggested to overcome any
limitations of clinical use of companion diagnostics and improve their
prognostic value or their contribution in therapy monitoring.



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