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International Journal of Molecular Sciences
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28 March 2025

Next-Generation Sequencing in Oncology—A Guiding Compass for Targeted Therapy and Emerging Applications

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1
“Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
2
Department of Medical Oncology II, “Prof. Dr. Al. Trestioreanu” Institute of Oncology, 022328 Bucharest, Romania
3
Department of Neurology, National Institute of Neurology and Neurovascular Diseases, 077160 Bucharest, Romania
4
General Surgery and Surgical Oncology Department I, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
Int. J. Mol. Sci.2025, 26(7), 3123;https://doi.org/10.3390/ijms26073123
This article belongs to the Special Issue New Insights into Gene Expression Regulation in the Next-Generation Sequencing (NGS) Era
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Abstract

Multigene sequencing technologies provide a foundation for targeted therapy and precision oncology by identifying actionable alterations and enabling the development of treatments that substantially improve clinical outcomes. This review emphasizes the importance of having a molecular compass guiding treatment decision-making through the multitude of alterations and genetic mutations, showcasing why NGS plays a pivotal role in modern oncology.

1. Introduction

The unwavering pursuit of cancer cures has led to meaningful advances in multi-omic investigations, paving the way toward therapy tailored to the molecular intricacies of the cells. After successfully targeting the BCR-ABL rearrangement in chronic myeloid leukemia in 1998, the concept of precision oncology became pivotal for the development of therapeutic interventions tailored to the molecular specifics of individual tumors. Over 200 targeted therapies are currently approved, as of December 2024 [], showing a growing interest in delivering the right treatment to the right patient at the right dose at the right time [].
Consequently, precise diagnostic tools capable of accurately identifying treatment-impacting biomarkers have been developed since Next-Generation Sequencing (NGS) became almost synonymous with precision oncology and targeted therapy guidance. In essence, NGS enables a comprehensive genomic evaluation by parallel sequencing large quantities of DNA fragments extracted from tissue or liquid samples, resulting in a high-throughput, high-yield technique capable of interrogating sensitive molecular events with an impactful meaning in the subsequent clinical management []. Due to high specificity, NGS is evaluated for the development of multicancer early detection (MCED) tests [].
NGS assays have received widespread institutional approval and are highly advocated in the current oncology guidelines on the pretreatment evaluation of a multitude of solid tumors [] (Table 1).
Table 1. Commercially available NGS assays in the treatment of solid tumors.
Current National Comprehensive Cancer Network (NCCN), European Society for Medical Oncology, and American Society of Clinical Oncology (ASCO) guidelines recommend NGS in patients with advanced lung, breast, colorectal, prostate, and ovarian cancer, with indications ever expanding with the development of novel drugs [,]. Our current review is intended as a broad argument for the value of NGS in various clinical scenarios and the specific molecular alterations that can be interrogated and specifically targeted for the treatment of solid tumors.

2. The Current Role of NGS in Solid Tumor Oncology

2.1. Challenging Established Classifications and Redefining Diagnostics with Precision Oncology

Multi-omic research from past decades has provided sufficient evidence to prove the transformative role of certain molecular alterations concerning tumor biology, prognosis, and therapy. Such a paradigm shift occurred in the WHO classification of gliomas following the cIMPACT-NOW updates, which highlight the meaningful impact of simultaneously profiling key genes for an accurate diagnosis. Consequently, the 2021 EANO Guidelines for the diagnosis and management of gliomas showcase the importance of broad molecular profiling and correct identification of prognostic and predictive biomarkers [,]. We summarize the recommendations for the molecular-driven diagnosis and treatment of gliomas in Table 2.
Table 2. Molecular markers for the diagnosis and management of gliomas, as recommended by the 2021 EANO Guidelines.
Another example is the treatment for some rare tumor types, which has already proven the symbiosis between targeted therapy and gene sequencing for precise treatment administration. Gastrointestinal stromal tumors (GISTs) originate from the interstitial cells of Cajal and express a wide array of molecular alterations, including KIT, PDGFRA, and SDH alterations, providing different treatment options that require mutational testing for adequate treatment. Furthermore, mutations such as PDGFRA D842V confer insensitivity to well-established treatment agents such as Imatinib and, as such, require a broad investigation of all known molecular alterations associated with GISTs to recommend the precise therapy [,,].

2.2. Guiding Compass for Tumor-Agnostic Tumors

The classical characterization of any cancer includes the location and tissue of origin as guiding elements for clinical management. With the possibility of interrogating for druggable molecular alterations, the concept of tumor-agnostic therapy has emerged as a new approach in oncology, emphasizing the specific driver of cancer growth as a treatment decider [,].
Although other methods exist for detecting aberrant mutations, such as FISH or RT-PCR, NGS is the only one that confers the advantage of a comprehensive genomic profile, including other targetable oncogenes. Furthermore, due to the high specificity and sensitivity, DNA NGS testing on formalin-fixed, paraffin-embedded (FFPE) tumor specimens is often used as the confirmatory test for FISH and RT-PCR.
In an encouraging report from Coquerelle et al., the researchers demonstrate improved access to clinical trials due to the better genetic profiling facilitated by NGS []. It is important to note that the pan-tumor paradigm shift was made possible through basket trials using NGS for patient inclusion, depending on specific molecular alterations, rather than prioritizing the tumor origin. Consequently, patients with rare and ultra-rare tumor types, as well as patients with carcinoma of unknown primary (CUP) or patients with multiple prior lines of therapy, have been eligible for targeted therapy, with improved clinical outcomes [,,,,,].
Table 3 summarizes the data from key clinical trials for NTRK and RET inhibitors, showcasing the benefit of comprehensive genome testing for drug development in the pan-tumor setting.
Table 3. Drug development in the tumor-agnostic setting—available data from key clinical trials for NTRK and RET inhibitors.

2.2.1. Neurotrophic Tyrosine Receptor Kinase (NTRK) Fusion-Positive

The three NTRK genes (NTRK1, 2, and 3) encode the tropomyosin receptor kinase (TRK) receptor family proteins responsible for different neural cell functions. Mutations in the NTRK genes (fusions most commonly incriminated) have been observed in solid tumors such as gastrointestinal cancers and gynecological, thyroid, lung, and pediatric malignancies [,,,].
The inaugural pan-TRK inhibitor Larotrectinib was approved following three pivotal clinical trials, LOXO-TRK-14001, SCOUT, and NAVIGATE, collectively enrolling 153 eligible patients, both adult and pediatric. Pooled analysis showed an Overall Response Rate (ORR) of 79% (95% CI, 72–85%), 16% showing Complete Response (CR), a median duration of response (DoR) of 35.2 months (59 of which had a DoR of >24 months), a median progression-free survival (mPFS) of 28.3 months, and median overall survival (mOS) of 44.4 months. [,,].
Although Entrectinib is also a first-generation, small-molecule inhibitor of NTRK, it is also a multikinase inhibitor of the ROS1 and ALK oncogenes. Approval in the tissue-agnostic setting stems from integrating the data from the ALKA-372-001, STARTRK-1, and STARTRK-2 trials, showing an ORR of 57% (95% CI, 43.2–70.8%), with four patients out of the 54 adult patients included in the trials showing CR. The median DoR (mDoR) was 10 months (95% CI, 7.1 months to not reached), with 56% of patients having a response of over a year. [,]. An updated integrated analysis of 121 patients with 14 tumor types and over 30 histologies indicated (after a follow-up period of 25.8 months) an ORR of 61.2%, mDoR of 20 months (95% CI, 13–38.2 months), mPFS of 13,8 months (95% CI, 10.1–19.9 months), and mOS of 33.8 months (95% CI, 23.4–46.4 months) [].
Repotrectinib is a novel-generation multitargeted tyrosine kinase inhibitor (TKI), with data available for ROS1-positive Non-Small Cell Lung Cancer (NSCLC) through the ongoing TRIDENT-1 trial. []. However, the inhibitor showcases activity for NTRK 1/2/3 fusions and is currently on trial in the tumor-agnostic setting (Table 2).

2.2.2. Rearranged During Transfection (RET) Fusion-Positive Cancers

The RET gene is located on chromosome 10 and encodes a transmembrane receptor tyrosine kinase that is involved in the normal embryogenesis of the kidney, the enteric nervous system, and spermatogenesis [,,,,]. Since the late 1980s, the proto-oncogenic role of RET has been identified and characterized in numerous cancer types, including thyroid, lung, and breast cancer, with RET alterations occurring in less than 5% of all cancer patients [,,].
Previously, RET fusions were targeted using multikinase inhibitors (e.g., Vandetanib). However, the development of selective RET inhibitors, such as Selpercatinib and Pralsetinib, has been advantageous in the pan-cancer treatment setting and received FDA approval due to improved specificity and potency [].
Selpercatinib is a small-molecule TKI targeting RET alterations (including mutations and fusions) [] that was FDA-approved after the results from the LIBRETTO-001 trial, which included patients with RET-altered tumors, and showed encouraging activity in NSCLC and medullary thyroid carcinoma, as well as other cancers (among 45 patients with non-NSCLC or thyroid carcinoma the ORR was 43.9%, 95% CI 28.5–60.3%) [,,]. In addition to Selpercatinib, Pralsetinib has also shown pan-cancer efficacy across RET fusion-positive solid tumors, with an ORR of 57% (95% CI, 35–77%) [,]. In the ARROW clinical trial. Further information regarding the LIBRETTO-001 and ARROW clinical trials regarding the specific treatment settings where Selpercatinib and Pralsetinib have been investigated are presented in Table 2.

2.2.3. Von Hippel–Lindau Disease

Von Hippel–Lindau (VHL) disease is a rare hereditary disorder (approximately one in every 27,300–39,000 live births) linked with the development of both benign and malignant neoplasms, including clear-cell renal carcinoma (RCC), pancreatic neuroendocrine tumors (pNETs), and CNS and retinal hemangioblastomas. The hypoxia-inducible factor inhibitor Belzutifan has been approved for the treatment of advanced tumors associated with the germline pathogenic variants of the VHL gene as a result of the LITESPARK-004 trial, which showed promising results, such as an ORR of 59% for RCC (including two CRs), and 90% for pNET, with an acceptable toxicity profile [,,,,].

2.2.4. Human Epidermal Growth Factor Receptor 2-Positive (Her2-Positive) Tumors

HER2 (also known as ERBB2 or Her2-neu) is a 185 kDa transmembrane protein belonging to the Epidermal Growth Factor Receptors family. It is encoded by the HER2 gene, which is situated on the 17q21 chromosome [,,]. Overexpression of the Her2-neu gene leads to a 40–100-fold increase in HER2 protein, which in turn leads to overexpression on the cellular surface []. Although the Her2 is an orphan receptor, the protein relies upon the binding of the extracellular domain of one of the other HER family receptors (HER 1, 3, 4 tyrosine kinases) with one of the 11 possible ligands to undergo heterodimerization (or even homodimerize when expressed at very high levels) and transphosphorylation of the intracellular domain. The phosphorylated products interact with multiple intracellular signaling pathways (such as the phosphoinositide-3-kinase/protein-kinase-B, PI3K/AKT, and anti-apoptosis pathway, for which HER2 is the most potent stimulator), regulating genes involved in cancer cell proliferation, survival, differentiation, angiogenesis, invasion, and metastasis [,,,,,,]. Although HER2 overexpression is classically defined through immunohistochemistry (an IHC3+ expression meaning positivity), the HER2 amplification can be interrogated in multigene assays and can be observed in a multitude of solid tumors, including breast, gastric, biliary tract, pancreatic, and lung tumors. As such, NGS can become a practical solution for a larger-scale adoption of anti-HER2 targeted therapy in the tumor-agnostic setting or after multiple lines of therapy have been exhausted [,,,].
The DESTINY-PanTumor-02 trial confirmed the pan-cancer efficacy of trastuzumab deruxtecan (T-Dxd) by treating 267 patients across different tumor cohorts (including endometrial, cervical, biliary tract, and pancreatic) with HER2 overexpression confirmed through IHC (IHC2+ or IHC3+) with the antibody-drug conjugate. The ORR result was 37.1% for all comers (all patients with centrally confirmed HER2 overexpression experienced a response to T-Dxd). However, the response was greater for patients with centrally confirmed IHC3+, with an ORR of 61.3% (95% CI, 49.4–72.4%). Across all cohorts, the mOS was 13.4 months (95% CI, 11.9–15.5 months), ranging from 5 months in the pancreatic cohort to 26 months in the endometrial cohorts. The T-Dxd therapy is not without risks; 40.8% of patients experienced Grade 3 or greater drug-related adverse events, and 10.5% experienced drug-related interstitial lung disease, which in three cases resulted in death [,]. Nonetheless, T-Dxd has received approval for the treatment of HER2-positive (IHC3+) solid tumors and is endorsed by guidelines for the treatment of HER2 overexpressing tumors [].
Similarly, the MYPathway HER2 basket trial supports HER2-directed therapy with the combination of Pertuzumab and Trastuzumab in HER2-positive (HER2 overexpressing, IHC3+, or HER2 amplified) solid tumors, achieving an ORR of 25.9% (notably, patients with IHC3+ expression exhibited an ORR of 41%, patients with IHC2+ expression had an ORR of 21.9%, and no response was observed for patients with no HER2 expression) [].

2.2.5. BRAF V600E-Mutated Cancers

The aberrant stimulation of the mitogen-activated protein kinase (MAPK) pathway through alterations of BRAF (specifically the substitution of valine with glutamic acid at position 600 of the protein, the BRAF V600E mutation) leads to oncogenesis in up to 3% of people diagnosed with cancer, mainly in thyroid cancer and melanoma. Furthermore, activation of MEK promotes tumor cell growth, proliferation, and survival, and, as such, dual inhibition of BRAF and MEK has been proposed as a therapeutic strategy in BRAF V600E-altered tumors [,,,,,,,,,,,].
After encouraging results from melanoma and NSCLC, the pan-cancer efficacy of Dabrafenib (BRAF inhibitor) and Trametinib (MEK inhibitor) has been evaluated in the Rare Oncology Agnostic Research (ROAR) trial, which indicated clinically meaningful responses in anaplastic thyroid carcinoma (ORR, 56%), biliary tract cancer (ORR, 47%), and gliomas (ORR, 31% for high grade, 69% for low grade), leading toward the approval and recommendation of the dual blockade in the pan-cancer BRAF V600E mutation-positive setting [,,,,,,].

2.2.6. High Mutational Burden Tumors

The quantitative measure of mutations in the tumor genome (measured as the number of mutations per megabase), as assessed by NGS, is currently under research as a novel positive predictive biomarker for immune checkpoint inhibitors, especially Pembrolizumab. The interest in assessing mutational burden is high, as estimations show that nearly 20% of all cancers have a mutational burden of ≥10 mut/Mb (TMB-H tumors), including melanoma and nonmelanoma skin cancer, and also bladder, lung, and small intestinal cancers [,,,,]. As such, compared to the other pan-cancer therapies discussed so far, NGS can be used as a quantitative assay to determine the predictive biomarker for immunotherapy rather than targeted therapy.
Following the KEYNOTE-158 trial, in 102 patients with tumor mutational burden TMB ≥ 10 mut/Mb, treatment with Pembrolizumab resulted in an ORR of 29% (95% CI, 21–39%), with mDoR not reached (half of the patients achieved a duration of response of over two years), mPFS of 2.1 months (95% CI, 2.1–4.1 months), and mOS of 11.7 months (95% CI, 9.1–19.1 months). A higher tumor mutational burden (i.e., ≥13 mut/Mb) correlates with higher response rates, with similar clinical benefits for patients, leading to the FDA approval of Pembrolizumab at the 10 mut/Mb threshold [,,].

2.2.7. Mismatch Repair Deficient (dMMR)/High Microsatellite Instability (MSI-H) Cancers

Similar to TMB-H tumors, dMMR/MSI-H cancers are associated with a hypermutable status, resulting from deficiencies in the mismatch repair genes leading to losses of genomic integrity. These alterations are linked with Lynch Syndrome and are frequently reported in endometrial, small bowel, colon, and gastric cancers [,]. Two PD-1 blockers, Pembrolizumab and Dostarlimab, have been FDA-approved for the tissue-agnostic setting, showing improved clinical outcomes [,,,,,,].
IHC typically determines dMMR/MSI-H status. However, NGS testing can detect mutations in the four key MMR genes (MLH1, PMS2, MSH2, and MSH6) and diagnose Lynch Syndrome, which is an autosomal dominant genetic disease. Thus, NGS can screen and monitor healthy first-degree relatives at risk for Hereditary Non-Polyposis Colorectal Cancer, Endometrial Carcinoma, and other associated cancers. Furthermore, NGS testing can offer a broader panel of actionable biomarkers, impacting further treatment.
Recently, PD-1 antagonists have shown impressive responses in the neoadjuvant setting []. Such promising results are desperately awaited in the treatment of locally advanced cancers, especially chemo-unresponsive tumors such as dMMR/MSI-H, where the prognosis remains poor despite multimodal efforts to find a cure []. Table 4 summarizes the prospective trials showing the added impact of immune therapy in the pre-surgical setting of dMMR/MSI-H tumors, including the possibility of having a watch-and-wait strategy for tumors showing a complete clinical response after the completion of neoadjuvant immunotherapy.
Table 4. Prospective clinical trials that are investigating immune checkpoint inhibitors as neoadjuvant therapy for MSI-H gastrointestinal cancers.

2.3. The Oncogenic Driver Landscape in NSCLC

Determining potential oncogenic drivers is a pivotal step in the diagnosis of NSCLC, as they are positive predictors for targeted therapy, and some are negative predictors for immune checkpoint inhibitors or chemotherapy. The modest response to immune therapy comes as an inherent feature of oncogene-driven tumors, which are characterized by low TMB, lack of neoantigens, and a microenvironment low on immune cells []. These key principles of therapy apply to approximately 60% (80% in the Asian population) of lung adenocarcinoma patients who are positive for an oncogenic alteration (Figure 1 presents the incidence for each oncogenic driver). As such, the comprehensive genomic evaluation offered by NGS is vital in the diagnostic work-up for locally advanced and metastatic NSCLC by identifying druggable alterations and screening for de novo or acquired resistance mechanisms [].
Figure 1. A schematic overview of the treatment options in different clinical scenarios, according to the molecular profile of NSCLC tumors. Indications for targeted therapy were collected from the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology, Version 4.2025, Published 14th of January 2025. Accessed 24 March 2025 (Available at: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf).
One of the most well-known examples is Epidermal Growth Factor Receptor (EGFR) mutations, present in 10–25% of NSCLC cases, more predominantly in adenocarcinomas, particularly among non-smokers, and more frequent in the Asian population []. A total of 90% of EGFR mutations are constituted by the deletion in exon 19 and the leucine–arginine substitution at codon 858 (L858R) and can be targeted by first- (Erlotinib, Gefitinib) and second-generation (Afatinib, Dacomitinib) EGFR inhibitors [,]. Unfortunately, the PFS of these drugs is largely dictated by the acquisition of a secondary point mutation, the substitution of methionine for threonine at amino acid position 790 (T790M mutation), conferring tumoral resistance to treatment []. The third-generation inhibitor Osimertinib also acts on this mutation, bypassing the resistance mechanism, and is now a pillar in the treatment of EGFR-mutated NSCLC as a first-line metastatic treatment [,]. Nonetheless, Osimertinib is also recommended as adjuvant and consolidation therapy after surgery or definitive chemoradiation, showcasing the importance of genomic profiling in pre-metastatic stages of the disease [,].
Similar to EGFR mutations, Anaplastic Lymphoma Kinase (ALK) (typically translocations) typically occurs in non-smoker NSCLC patients with adenocarcinoma histotype in approximately 3–5% of NSCLC cases [,]. Similarly, the drug development of ALK inhibitors had to overcome acquired resistance mechanisms such as L1196M (which confers resistance to Crizotinib) or ALK G120R/del (which confers resistance to both first- and second-generation ALK inhibitors), leading to the development of Lorlatinib [,]. ALK inhibition can also be used in the adjuvant setting, as shown in the ALINA trial, which showed overwhelming benefits for postsurgical treatment with Alectinib [].
EGFR and ALK mutations are two classic examples of oncogene drivers that must be identified and specifically targeted to substantially benefit patients’ clinical outcomes. As more oncogenes are discovered and therapies are developed, the need for a sensitive investigation to confirm the eligibility to specific targeted therapy tailored for these alterations will become more imperative. Consequently, NGS will become essential, both as a tool for initial diagnosis and indispensable in the later stages of the disease for profiling tumor alterations and correctly choosing treatment by considering druggable mutations and acquired resistance mechanisms. It is thus vital to encourage the development of Molecular Tumor Boards to coordinate treatments, deliver precise therapies, and mitigate the economic burden associated with NGS and novel therapies []. Figure 1 and Table 5 provide an overview of the targeted therapy landscape for NSCLC.
Table 5. Pivotal trials in oncogenic-driven NSCLC with targeted therapy, trial design, objective response rate (ORR), median progression/disease-free survival in months (mPFS/DFS), with hazard ratio (HR) if the trial was Phase 3, and median overall survival (mOS) in months, with HR if the trial was Phase 3. Indications for targeted therapy were collected from the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology, Version 3.2025 Published 14th of January 2025, Accessed 24 March 2025 (Available at: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf).

2.4. Investigating Homologous Repair Deficiencies—Treatment Avenues and Hereditary Cancer Risk Evaluation

Homologous recombination deficiency (HRD) describes the cellular incapacity to repair DNA damage provoked by endogenous or exogenous cancerogenic agents. This results in the accumulation of double-stranded breaks in the DNA helix, increasing the likelihood of developing cancer. HRD can result from germline (as observed in hereditary cancers) or somatic mutations of a multitude of genes, BRCA1 and BRCA2 being the most well-known, due to the increased likelihood of developing breast (56–65% for BRCA1, 35–57% for BRCA2) or ovarian (20–50% for BRCA1, 5–23% for BRCA2) cancers, but also pancreatic, prostate, or colorectal cancers, and with an increased likelihood of synchronous cancers [,,,]. Other genes have also been linked to HRD, such as ARID1A, ATM, ATRX, BAP1, BARD1, BLM, CHEK1/2, MRE11A, NBN, PALB2, RAD50, RAD51, and WRN, with varying prognostic significance, indicating that evaluating HRD requires interrogation for multiple genetic anomalies simultaneously [,,].
HRD-positivity implies a positive prediction toward treatment with poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi), which have markedly improved outcomes in both adjuvant and metastatic settings [] (Table 5). Furthermore, HRD positivity has implications for the patient’s family members, as germline mutations cause hereditary cancers in first-degree relatives, requiring inclusion in screening programs and/or prophylactic interventions such as mastectomy or bilateral oophorectomy [,]. These interventions need to be tailored according to the cancer penetrance of the alteration detected, and multiple studies have noted the importance of multi-gene panel tests for the detection of hereditary cancers [,].
A summary of the pivotal trials regarding PARPi is presented in Table 5. Notably, the inhibitors show activity in BRCA1/2 mutations and the other alterations associated with HRD, showcasing the benefit of a broader investigation. The clinical benefits of improved DFS, PFS, and OS in either adjuvant or metastatic setting cannot be overlooked, as BRCA1/2 mutations are typically associated with poorer prognosis in breast, ovarian, and prostate cancers [,,]. As such, treatment with PARPi offers a much-needed treatment solution for a group of high-risk patients and NGS enables the precise inclusion of the target population, as well as investigating the familial risks for developing cancer (Table 6).
Table 6. Pivotal Phase 3 trials in PARP inhibitor therapy across cancer types, including trial design, median progression/disease-free survival in months (mPFS/DFS), hazard ratio (HR), and median overall survival (mOS) in months with HR.

2.5. Bridging the Hormone–Chemotherapy Gap in HR-Positive Advanced Breast Cancer

After the development of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i), one of the unmet needs in the treatment of hormone receptor-positive (HR+) advanced breast cancer (ABC) was to find therapies that could provide meaningful benefit beyond progression due to the relative chemoresistance of these tumors. Although there have been investigations within the immune-mediated mechanisms of endocrine resistance, so far, immunotherapy is still under investigation and controversial [,]. As such, targeted therapies play an important role, particularly in the PIK3/AKT pathway, with PIK3CA mutations prevalent in HR+ breast cancer (34.5%) and AKT1 and PTEN mutations restricted to this subgroup []. Furthermore, the ESR1 mutation is of particular interest, as a definitive result yields the certainty of endocrine resistance, and NGS provides a very high diagnostic accuracy [].
The results of the pivotal trials on targeting this pathway are summarized in Table 7. It is important to note that these alterations should be investigated together with BRCA1/2 mutations (see Section 2.3) for treatment with PARPi and other tumor-agnostic therapies (see Section 2.2.), resulting in an increased need for multigene examination in this subset of patients.
Table 7. Pivotal clinical trials involving targeted therapies of PIK3CA/AKT1/PTEN alterations and ESR1-mutation.

3. Discussion

The need for significant developments in the precision oncology era requires tools such as NGS for the therapeutic management of oncologic patients. Several reports have provided evidence for the high-accuracy diagnostic value of NGS [,].
It is important to note, however, that several pitfalls may alter the diagnostic accuracy of NGS, particularly in the pre-analytical phase. As such, the tissue blocks selected for analysis must represent a substantial portion of the tumor (at least 20%) for biomolecular analysis viability []. Furthermore, factors such as time to fixation, duration of fixation, and the conditions for tissue storage will significantly affect the nucleic acid integrity of the tumor tissue []. Nonetheless, sequencing provides challenges as well, with risks including degradation by RNases, cross-linking, and fragmentation [,]. These pitfalls need to be considered in the evaluation of the NGS workflow, but disadvantages such as long turnaround times, the need for specialized personnel, and higher costs are outweighed by the pivotal contribution that NGS brings to oncological management.
As the article written by Zalis et al. remarks, coupling NGS testing with liquid biopsies offers significant advantages, such as an alternative to surgical tissue biopsies in a non-invasive manner (reducing the patient discomfort and risk of complications), monitoring cancer progression and response to treatment in real time (allowing for timely adjustments in therapy), detecting minimal residual disease, and identifying resistance mechanisms, thus guiding the selection of alternative treatments [].
Furthermore, growing evidence suggests that targeted therapy improves response rates and clinical outcomes []. A comprehensive literature review carried out by Gibbs et al. indicates a significant impact on survival across tumor types for NGS-informed treatment [].
Admittedly, NGS and the rise of targeted therapy indications might prove expensive. However, there is growing evidence showing the potential for cost-effectiveness under specific reimbursement policies that would permit adequate access to novel therapies []. Furthermore, most targeted therapy options are safer to administer than ChT, with fewer side effects, and require fewer days of hospitalization, as most treatments can be administered orally. This can prove advantageous for the patient’s compliance with treatment, even in adverse situations and unforeseen circumstances, such as COVID-19, which can limit access to hospitals [].
Compelling economic arguments can also include the dramatic decrease in NGS costs since the early 2000s. Technological advancements and scale economics decreased from $100 million to less than $1000 in some cases. Unfortunately, costs can still prove prohibitive in low- and middle-income countries, especially if a lack of reimbursement means out-of-pocket costs for the patient []. This is not to say, however, that NGS analysis and subsequent treatment decisions are not cost-effective, as some systematic reviews have demonstrated financial advantages for NGS-guided treatment decisions [,]. Consequently, efforts to develop cost-minimizing workflows for testing, initiatives to develop genomic research capacity, collaborative efforts for genomic data sharing and analysis, and implementation of guidelines mindful of the potential financial toxicity incurred would provide great benefit in the large-scale adoption of NGS testing [,].

4. Conclusions

In conclusion, NGS has become synonymous with precision oncology, guiding treatments with unparalleled precision and assisting in developing new treatment strategies. Integrating artificial intelligence, collaboration in Molecular Tumor Boards, and continued policy support will be essential for harnessing its full potential and ensuring equitable access to genomic-driven therapy for all patients. Guidelines from the ESMO, NCCN, and ASCO all recommend multigene panel-based genomic testing, and the continuous effort to integrate NGS testing is pivotal for precision oncology.

5. Future Directions

Our narrative review showcases the benefits of NGS in guiding diagnosis, targeted therapy, and immune therapy by interrogating multiple complex genomic alterations. The development of new therapies, such as CAR-T cell therapy for solid tumors, may result in new opportunities for NGS adoption. Trials such as the SPEARHEAD-1 in synovial sarcomas show promising results for the adoption of CAR-T cell therapies such as afamitresgene autoleucel and require molecular profiling for melanoma-associated antigen A4 (MAGE-A4) expression and HLA typing []. Further trials are expected for such therapies in solid tumors, and the pivotal role of NGS in finding valid targets and HLA typing can play a significant role in this expansion. Furthermore, the considerable impact of NGS in interrogating for polymorphisms of the same gene can be extremely useful in identifying genetic variations of pharmacogenes, implying a near future where therapy toxicity can also be adjusted according to the individual characteristics of each patient []. It is, therefore, highly likely that NGS will become synonymous with the practice of precision oncology in the management of solid tumors.

Author Contributions

Conceptualization, L.N.G. and R.M.A.; methodology, R.M.A. and O.G.T.; software, M.-A.P.; validation, O.G.T., L.N.G. and L.S.; formal analysis, L.N.G.; investigation, M.-A.P.; resources, R.M.A.; writing—original draft preparation, M.-A.P. and I.B.; writing—review and editing, I.B. and M.-A.P.; visualization, I.B.; supervision, L.N.G. and L.S.C.M. All authors have read and agreed to the published version of the manuscript.

Funding

This work was funded by the EU’s NextGenerationEU instrument through the National Recovery and Resilience Plan of Romania-Pillar III-C9-I, section I5. Establishment and operationalization of Competence Centers PNRR-III-C9/2022/MCID/I5, managed by the Ministry of Research, Innovation, and Digitalization, within the project entitled “Creation, Operation, and Development of the National Center of Competence in the Field of Cancer”, contract no. 760009/30 December 2022, code CF 14/16 November 2022.

Acknowledgments

The publication of this paper was supported by the University of Medicine and Pharmacy Carol Davila through the institutional program Publish not Perish.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

AEAdverse Events
ALKAnaplastic Lymphoma Kinase
BRAFB-Raf Proto-Oncogene
BRCA1/2Breast Cancer Gene 1/2
CDK4/CDK6Cyclin-Dependent Kinases 4 and 6
cfDNACirculating Free DNA
ChTChemotherapy
CIConfidence Interval
CNSCentral Nervous System
CRCColorectal Cancer
DFSDisease-Free Survival
dMMRDeficient Mismatch Repair
DoRDuration of Response
EGFREpidermal Growth Factor Receptor
EREstrogen Receptor
ERBB2 (HER2)Erb-B2 Receptor Tyrosine Kinase 2 (also known as HER2)
ERBB3Erb-B2 Receptor Tyrosine Kinase 3
ESCATEuropean Society for Medical Oncology Scale for Clinical Actionability of Molecular Targets
ESR1Estrogen Receptor 1
FFPEFormalin-Fixed, Paraffin-Embedded
FISHFluorescence In Situ Hybridization
FGFR1/2/3Fibroblast Growth Factor Receptor 1, 2, and 3
HER2Human Epidermal Growth Factor Receptor 2
HRHazard Ratio
HR+Hormone Receptor-Positive
HRDHomologous Recombination Deficiency
HRRHomologous Recombination Repair
IHCImmunohistochemistry
KITKIT Proto-Oncogene, Receptor Tyrosine Kinase
KRASKirsten Rat Sarcoma Viral Oncogene
mDoRMedian Duration of Response
mDoTMedian Duration of Therapy
METMET Proto-Oncogene
MLH1MutL Homolog 1
mOSMedian Overall Survival
mPFSMedian Progression-Free Survival
MPRMajor Pathological Response
MSIMicrosatellite Instability
MSI-HMicrosatellite Instability-High
MTCMedullary Thyroid Carcinoma
mut/MbMutations per Megabase
NCCNNational Comprehensive Cancer Network
NGSNext-Generation Sequencing
NRNot Reached
NTRKNeurotrophic Tyrosine Receptor Kinase
NSCLCNon-Small Cell Lung Cancer
ORRObjective Response Rate
OSOverall Survival
PARPiPoly (ADP-ribose) Polymerase Inhibitor
PDProgressive Disease
PD-1Programmed Death-1
PDGFRAPlatelet-Derived Growth Factor Receptor Alpha
PFSProgression-Free Survival
PIK3CAPhosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha
PTCPapillary Thyroid Carcinoma
PTENPhosphatase and Tensin Homolog
q3wEvery 3 Weeks
RETRearranged During Transfection
ROS1ROS Proto-Oncogene 1
RTRadiotherapy
SCLCSmall Cell Lung Cancer
SoCStandard of Care
TMBTumour Mutational Burden
TKITyrosine Kinase Inhibitor
TMETotal Mesorectal Excision
TRKA/B/CTropomyosin Receptor Kinase A/B/C
TSC1/2Tuberous Sclerosis Complex 1 and 2
VHLVon Hippel–Lindau

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Chicken Primordial Germ Cells Do Not Proliferate in Insulin-Lacking Media
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