Significance of Next-Generation Sequencing (NGS) in Prognosis and Treatment of Cancer

*Lopez AP
Department Of Genetics, Molecular Biology Laboratory, Universidad De Buenos Aires, Argentina

*Corresponding Author:
Lopez AP
Department Of Genetics, Molecular Biology Laboratory, Universidad De Buenos Aires, Argentina
Email:aplopez@prensamedica.com.ar

Published on: 2020-12-29

Abstract

Many Technical developments for genome sequencing leads results the application of next-generation sequencing to oncology have cover the route for molecular profile-based individualization of cancer patient care. Although recent research findings provide evidence that favors this method in certain forms of advanced cancer, based on uses of next-generation sequencing trials in the labs is still an unresolved topic. Clinical research is quickly changed, from Master protocols, and platform trial to clinical oncology research with adaptive design accuracy, genomic-molecular information also takes the place of biomarkers traditional objective validation processes. Nowadays, doctors need to conscious about of the available clinical results support these latest next-generation sequencing and biomarkers experiments to utilize at the point of time from a crucial point of aspect.A systematic guide for the implementation of Clinical Cancer Detection in authentic routine practice includes the status of present targeted drugs will be successful upon molecular modifications needed, now the next-generation sequence trails widely accessible.

Keywords

Cancer Therapy, Personalized medicine and targeted therapy, Next-generation sequencing and precision oncology

Introduction

Precision oncology is a type of medicine that used to treat cancers aimed that specified individual patients based on a biomarker, genetic, psychosocial, or phenotypic features that differentiate one patient from other patient based on exhibition of different cancer [1]. Moreover,the concept is not uniquefor oncology that incorporates lead of the latest developments for accessing the analysis data in genome sequencing, as well as offering an unparalleled chance to raise clinical practice for personalized precision patient care [2].

To ensure that cancer victims receive the right care dosage at the specified time with minimal adverse repercussions and effectiveness, thedeveloped data for cancer has reveals the initial walkregarding precision oncology [3]. Althoughtamoxifen use for estrogen receptor in breast cancer was an early precedent for precision oncology[4], trastuzumab and imatinib drugs for precision cancer medicines directly approved against the molecular goal for the first time. The number of actionable changes with subsequent targeted therapy has been gradually rising over the next 20 years, including BRAF, ALK like complex genetic impression.

Several reasons for therapeutic and diagnostics, molecular testing handier in clinical method to identify genomic alterations. As a rule, when outcomes can affect clinical management, molecular testing should be ordered.

64 modified molecules and 24 molecular alterations available as an anticancer therapy aimed to treat cancer at the year of 2019. Significantly, the identification of the alteration was sufficient in 19 of these to effectively suggest a specific medication.The microsatellite and tropomyosin receptor kinase fusionuncertainty were authenticated as biomarkers of histology-agnostic for FDA acquiescencerespectively entrectinib, larotrectinib and pembrolizumab. In some but not all NGS platforms, these markers are detected, highlighting the requiredto the clinical researchers to identify the variations allyingobjectiveslikely to observe while initiating NGS testing in various tumor types.

European Society for Medical Oncology has developed A Scale of Clinical Actionability for Molecular Targets, which distinguishes 6phases for evidence based clinical testing for molecular targets based on the consequences ofcases [5]. It has been calculated that based on patient’s number registered for genome-driven therapy was 5 percent in previous and recently 2006-2018 8.33 percent. The expectedgrowth inclinical trials has improved 0.7% to 4.9% in 2006-2018 [6].

Multigene panels make it possible to organize mutation trends into mutational identities [7]. At present, homologous recombination impairment, MSI, and TMB are the most common. Flawed DNA service pathways cause HRD and it is correlated with the somatic exchange, addition/removal, and reconfiguration trends. Therefore, a system named "HRDetect," that defines HRD tumors, has been developed. These tumors may be prone to both PARP and PARP inhibition. TMB, which may be correlated with a reaction to immunotherapy, may also be quantified using NGS. Pembrolizumab was also accepted in patients with MSI-high tumors. However, these kinds of factors require complete scientific validity in theoretical cancer administration [8].

Multigene coding avoids the execution of many single sequential trials with either the advantage of preserving tissue specimen decreasing delay and leading to a patient the best effective new treatment [9]. Aimed councils depend on amplicon or hybridization grab dependent on NGS and shows strong outcomes in the detection of single nucleotide differences and configurations or removals in several clinical activities. This may recognize drug-like alterations that in certain malignancies show benefit.

The MSK-IMPACT and FoundationOne CDx test defined as major FDA molecular characterization NGS tests that analyze a higher set of genes at a time. FDA-accepted several different NGS assessments that focus on a specific community of genes. Those are available to lung cancer with Oncomine Dx, the colon cancer was treated by Illumina Extended RAS Panel.

There are other NGS tests in progress. Caris MI Transcriptome CDx is an in vitro diagnostic test focused on next-generation sequencing that uses formalin-fixed paraffin-embedded (FFPE) RNA isolated from tumor tissue to detect structural rearrangements. The Breakthrough System classification for the identification of FGFR gene fusions in solid tumors was obtained in 2019. In 2019, the FDA also issued the Breakthrough System Classification for the pan-cancer assay of Illumina, TruSight Oncology 500, which uses tumor samples of DNA and RNA to recognize small variants of DNA, fusions, and splice variants, as well as tumor mutational burden (TMB) and microsatellite instability (MSI).

The radical cost reduction of NGS platforms indicates that testing with a 300-gene panel could have a comparable cost shortly to testing 5 or 6 person alterations[10]. In future evaluations, the knowledge produced, although not always immediately available, can prove of extreme value.Genetic test evaluations have historically been mostly controlled at the national level in Europe [11].

The identification of gene alterations in NGS has many restrictions. Tumor heterogeneity, either static (in the tumor tissue) or dynamic (in different tumor biopsy-plasma sampling or plasma sampling time points), and various sequencing techniques, can be correlated with differences. A recent analysis of tumor and replicate plasma sample concordance together with orthogonal ctDNA assays showed that discordance was due to technical variations to a lesser extent to biological factors such as indeterminate potential clonal hematopoiesis and tumor heterogeneity [12,13].

In more cases where a primary biopsy might conduct years before an advanced disease emerged, the tissue might not be in a good state of conservation for the NGS examination. DNA derived from FFPE cancer tissue samples of surgical specimens older than 7 years has been indicated to be inadequate for NGS analysis [14]. Fresh biopsies should be performed in these situations if required, or plasma NGS must be suggested.

The presence of cancer-associated mutations in normal tissue is perhaps the most important and still not completely understood limitation for NGS testing [15]. In normal tissues and other benign circumstances, mutations typically seen in cancer, commonly referred to as 'driver mutations,' are frequently mutated but seldom develop to malignancy. Abnormalities in normal tissues also cluster in functionally important parts of the gene associated with cancer, such as DNA-binding domains or regions involved in protein-protein interactions, in a pattern nearly identical to that found in the tumor sequencing data for the distribution of mutations. This is considered a natural aging phenotype and may be associated with age-related decreased effectiveness of normal mechanisms of tumor suppression, such as touch inhibition, senescence, or immune surveillance.

To conduct observational studies that gather the experience of many patient outcomes and to assess the real usefulness of these profiling’s based on the ESMO and FDA criteria. There is an urgent need to organize and homogenize NGS tests and NGS results reports.

A cautious approach to generalized NGS testing has been expressed by some scholars, who have indicated that NGS could currently be primarily useful in managed laboratory environments or clinical trials, where off-label administration of costly drugs is confined to prospective cohorts of patient registries [16], considering that only a minimum of cancer patients derive a direct benefit from matched care, they support the continuation of an investigational strategy for NGS for specific oncology based on emerging biomarkers [17].

On the other hand, recommend that regular upfront NGS testing should be used for all patients with metastatic cancer with the restricted standard of care options[18,19]. Moreover, the use of multiplatform technologies tends to identify a higher number of possible targets than traditional consecutive molecular testing, which may result in a greater likelihood of finding an appropriate corresponding drug[20]. Also, NGS testing may recognize signatures of 'hypermutations' or DNA damage repair that can predict a response to immunotherapy (TMB, MSI), which would not be detected afterward.

For some diseases in which a first-line decision relies on several molecular markers, such as advanced non-small cell lung cancer, the use of a diagnostic NGS panel has become increasingly desirable because of the number of actionable gene alterations and the opportunity to obtain all therapeutic knowledge at the same time [20]. In this environment, the evidence that the specimens most frequently available for advanced lung cancer have a low tumor cell content is very relevant [21]. Most tissue samples submitted for clinical testing were small in one analysis of 1402 NSCLC samples [22], and the NGS test used produced a high success rate for reporting 5 or more biomarkers on core needle biopsies and 5 or more on FNAs.

Unusual cancers are those found in a limited number of patients and there is often no establishment of routine second-line care. These malignancies are also not studied in traditional phase III clinical trials that assess the value of upcoming therapies because of their rarity. Some sources include unknown primary cancers of the biliary tract, sarcomas, mesothelioma, and cancer.

Cisplatin-gemcitabine combination chemotherapy is the reference first-line treatment regimen for biliary tract cancers, but no standard second-line therapy exists. The genomic variations between intra-, extrahepatic cholangiocarcinoma, and gallbladder cancer have been highlighted by mutation profiling [23]. In a series of 75 patients with cholangiocarcinoma, NGS-based research was performed. There were major variations between intrahepatic and extrahepatic cholangiocarcinomas in gene expression. In intrahepatic cholangiocarcinomas, IDH1 and DNA repair gene alterations occurred more frequently, while ERBB2 gene alterations occurred in the extrahepatic community. In both forms of cholangiocarcinomas, BAP1 and FGFR gene pathway alterations occurred. A clinical advantage was observed for inhibitors of EGFR, FGFR, C-met, B-RAF, and MEK [24].

The average 15% of gallbladder cancers include Her2/neu amplification and may be treated with antiHER2 therapies, and an estimated 10-15% of cholangiocarcinomas have mutations in DNA repair and could be contenders for immune therapies. The MOSCATO research separately analyzed 43 cases of progressive biliary tract cancer and succeeded in administering molecular targeting agents in 18 cases, six of which have been an objective response [25].

Cancers are a diverse group of rare malignancies with more than fifty recognized subtypes, and the majority of NGS identified mutations are non-drivers and do not convert into patient clinical benefit[26]. For a person with few treatment options, although a clinical study based on NGS-derived data could give the possibility of experimental drugs being treated.

A recent analysis of previous papers using NGS in patients with Cancers of Unknown Primary (CUP) shows that 30 percent of patients reported mutations of possible therapeutic relevance [27]. The use of NGS and precision medicine is to guide a specific clinical trial to patients. This course includes an organized system of networks for clinical trials and new designs for clinical trials. There are current ongoing advances in the design of clinical early-stage cancer trials, such as rapid phase 1 dose-escalation studies accompanied by exceptionally expansion cohorts, or preliminary research, such as adaptive studies with basket and umbrella designs to improve the co-development process of biomarker-drug [28].

Single-gene sequencing has been routinely replaced with NGS sequencing only in a variety of practices thus the frequency of NGS research is markedly regionally different. Future concerns that will need to be resolved soon will include determining who can provide support for NGS research outside government insurance constraints, improving test reproducibility, improving the proportion of experiments that can generate a significant outcome, and improving therapeutic benefit prediction algorithms.

Conclusion

A new layer of sophistication is introduced to everyday clinical decision-making by NGS-enabled precision oncology. We have shown that NGS is most suitable for patients with advanced cancer in which several molecular targets are commonly known, particularly when they are useful in initial therapy. Also, NGS testing can help navigate patients to clinical trials, and in rare cancer patients, it can provide individual choices. Currently, NGS might be less suitable for other cancers because either the likelihood of detecting a target mutation is low, the cancer is at an early stage with known and successful types of conventional therapy, or the patient has an irreversible illness with a rather limited life span. As in every other laboratory examination, before ordering an NGS test, physicians and patients must be confident that their outcome would affect the therapeutic plan.In any event, as indicated, standard single-gene molecular testing must always be carried out as significant therapeutic targets could potentially be missed if no molecular tests were performed. Clinical studies have shown that NGS research can affect patients' response rate and progression-free survival and can therefore be a very beneficial strategy for new indications of molecularly targeted therapy. Primary factors responsible for improved outcomes in precision-oriented clinical research include the refinement of the studied molecular pathways, the development of molecular tests that incorporate transcriptomic and immunohistochemistry standardized genomic tests, the selection of more active targeted agents, the design of combinations of targeted agents, as well as other types of therapy, and the provision of early care.

To help with the understanding of ambiguous molecular outcomes that are often seen with NGS research, the interdisciplinary discussion is very relevant. Decide which is the best tissue to perform NGS, when is the right time to test, and if there are NGS clinical trial designs that allow for the use of control groups are significant unresolved problems that will need to be tackled in the future. Final twocritical aspects of the treatment that have raised ethical questions are the use of full informed consent before NGS testing and the communication of NGS reports to patients, which must always be discussed by practicing oncologists when ordering an NGS test.

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