Introduction in its label and this therapeutic

IntroductionCompaniondiagnostics are biomarker tools (usually quantification of gene expression,protein levels and qualitative detection of polymorphisms associated with adisease) to individualize and guide a therapy1. They are oftenapplied in order to monitor a therapy, to evaluate the risk/benefit ratio for apatient and to determine if a patient is likely to benefit from a treatment oris at high risk of getting side effects9. Companiondiagnostics are often combined with diagnostic methodologies, which not onlyindicate the target, but also the off-target effects of a drug, predictingadverse effects caused by the drug9.They areoften developed either through retrospective data of clinical studies3or simultaneously with drugs (either chemotherapeutics or monoclonalantibodies), the efficacy and safety of which they are designed to predict foreach individual patient. Companion diagnostics as assays are clinicallyvalidated during late clinical phases of the corresponsive drug, where they dividepatients into groups according to their variability in response to the drug, inorder to become regulatory approved at the same time with the drug and monitorthe therapy.1A companiondiagnostic should refer to a particular therapeutic product in its label andthis therapeutic product should require undergoing the companion diagnosticbefore being prescribed.

2 In terms of device, drugresponse prediction and therapy monitoring there are several types of companiondiagnostics: in vitro assays in biopsy materials (immunohistochemistry,fluorescence in situ hybridization) or in whole blood (genetic tests) or imagingtools, screening assays that detect genetic polymorphisms, theranostics thatpredict patient’s phenotype and his/her response to a treatment, prognosis andrecurrence tests that predict the progression of a disease and monitoringassays that determine ongoing efficacy and the suitable dose of a medicine fora patient.2Main partCompanion diagnostic for Herceptin(trastuzumab)Initially,companion diagnostics were developed to guide the use of oncology drugs,although rapidly they found application in various therapeutic areas. 2The first companiondiagnostic to be developed was Herceptest. HER2 (human epidermal growth factorreceptor 2) is a tyrosine kinase receptor, encoded by the ERBB2 gene, found overexpressed in breast cancer. Herceptest includesan immunohistochemistry assay, estimating the HER2 expression, in formalin-fixed,paraffin-embedded (FFPE) breast cancer tissue specimens and FFPE specimens frompatients with adenocarcinoma of the stomach and a fluorescence in situhybridization (FISH) assay to quantitatively evaluate determine ERBB2 gene amplification in the samespecimen11,12.Herceptestis used to and categorize breast cancer patients according to risk forrecurrence and to determine breast cancer patients who are expected to respond totrastuzumab treatment based on the score that is gained in the IHC and FISHassays and that indicates the intensity of staining in accordance withpercentage of stained tumor cells)11,12.

 Companion diagnostic for Pembrolizumab (Keytruda)Programmeddeath receptor-1 (PD-1) is expressed on the surface of T-cells and wheninteracts with PD-1 ligand-1 being overexpressed in tumor cells of5 patientsnon–small cell lung cancer (NSCLC), the tumor cells evade immune attack andsurvive. Pembrolizumab is a monoclonal antibody that targets PD-1 andinhibitsbinding of PD-1 with its ligand, exerting this way an antitumor effect.5IHC 22C3pharmDx test, (Dako) is an approved companion diagnostic in advanced NSCLC, whichis used to predict which patients are most likely to respond to treatment withpembrolizumab. More precisely, it is a PD-L1 immunohistochemical assay which isapplied in formalin-fixed, paraffin-embedded (FFPE) tumor-tissue sampleswith at least 100 viable tumor cells of patients with NSCLC and uses the 22C3anti–PD-L1 mouse monoclonal antibody and hematoxylin as a staining agent. Incase a patient with NSCLC undergoes this test and demonstrates a minimum TPSscore of 50%, which means that the membrane of 50% or more of viable tumorcells is partially or completely stained at any intensity, this patient is eligibleto treatment with pembrolizumab.

As with most companion diagnostics, however, there isdoubt regarding the prognostic value of this companion diagnostic, as it can beaffected by the presence of inflammatory cells in the sample, the heterogeneousexpression of PD-L1 in tumor cells and the immune alteration of tumor cells, atumor sampling error and the tumor type.5Companion diagnostic for PARP inhibitors Homologous recombination (HR) consists of pathwaysthat contribute in the repair of DNA double-stranded breaks and interstrandcrosslinks6. BRCA2 and BRCA1 are known tumor suppressor genesthat involve not only in DNA replication and transcription regulation, but alsoin HR repair8.

Mutations in BRCA2 and BRCA1 genes are considered to be implicated in hereditary breastand ovarian cancer6.Epithelial Ovarian Cancer (EOC) tumors with Homologous Recombination Deficiency(HRD) exhibit sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors inclinical practice7, as PARPinhibition in combination with Homologous Recombination Deficiency in HRD cells,such as BRCA mutated cells, leads to DNAdamage and synthetic lethality (tumor cell death by accumulation of non-lethal DNArepair failures)8. Next generation sequencing (NGS) is applied inorder to investigate genomic alterations in EOC which are linked to HRD and topredict response to PARP inhibition, identifying patients for precisionmedicine7.Myriad’sBRACAnalysis CDx™ is an in vitro diagnostic device using whole bloodsample from a patient, approved by FDA. It consists of two in vitro assays thatdetect and classify germline variants in five categories: Polymerase chainreaction (PCR) or Sanger sequencing to detect small inser­tions and deletions (?5basepairs) and single nucleotide polymorphisms (SNPs) in exons and exon/intronjunctions of BRCA1/2, and multiplexPCR to detect large rearrangements in BRCA1 and BRCA2. Therefore, this companiondiagnostic contributes in identification of EOC patients with detrimental BRCA1/2 polymorphisms and allows forprediction of the patients who are most likely to benefit from olaparib (PARPinhibitor) 8.

Restrictionsregarding the application of this assay is that it is limited in detection onlyof known genetic polymorphisms. Another limitation is that this technique isunable to distinguish gene dupli­cation from triplication and sometimes couldprovide false negative results due to uneven allele amplification (in case ofpresence of SNP at a primer site) 8.Implications for clinical care -Impact of companiondiagnostics on efficacy-safety of targeted anticancer-therapyAccording toresults coming from analysis that consisted of randomized clinical trials(RCTs) estimating efficacy and toxicity of 28 targeted anticancer-agents (approvedby the US Food and Drug Administration since year 2000) with or withoututilization of a companion diagnostic, it was found that companion diagnosticswere linked with higher tolerability and improved safety.3Implications for clinical care – Limitations Limitationsin application of companion diagnostics derive either from the molecular assay9or improper handlings independent of the diagnostic test such as falseisolation of tumor sample5. Companiondiagnostics assess the presence of a biomarker qualitaitively and quantitatively(gene expression or gene polymporphism), but provide little information aboutthe localization of a biomarker. Thus, diagnostic imaging (such as magneticresonance imaging-MRI or PET) is necessary for effective application of acompanion diagnostic test, especially in monitoring cancer patients. Furthermore,companion diagnostics evaluate only one biomarker, while resistance to a drugin some cases can be predicted by taking into account multiple biomarkers (ie. EGFRexpression and KRAS mutations predict both eligibility to EGFR inhibitors).

Thisfact in combination with possible low sensitivity of some companion diagnosticsset limitations in their use. These limitations require additional data, gainedfrom other assays (such as Next Generation Sequencing or imaging methods) inorder to be overcome and when they get ignored, misleading inaccurate resultsarise9. Indeed, false negative results wererecorded regarding identification of EGFR mutations in patients with non smalllung cancer (NSLC), due to tumor sampling error or failure to report andidentify limitations of testing assays, resulting in false ineligibility ofthese patients to be enrolled in phases 2 and 3 of a novel targeted therapy10.ConclusionCompanion diagnostics seem to be animportant tool regarding drug development and precision medicine in clinicalpractice. It seems that an increase in the number of companion diagnostics, asexpected in the near future in the field of oncology, would lead to a morecost-effective pharmacotherapy benefiting patients and healthcare system1.However, there are limitations in use of companion diagnostics, which mayresult in misleading results.

Therefore, in order for the companion diagnosticsto provide accurate and true results, the awareness of the limitations of thecompanion diagnostics assays should be raised. Moreover, a combination of themwith an alternative procedure (NGS or an imaging method) suggested to overcome anylimitations of clinical use of companion diagnostics and improve theirprognostic value or their contribution in therapy monitoring. 


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