Nasopharyngeal Carcinoma - Nasopharyngeal Carci

Download as pdf or txt
Download as pdf or txt
You are on page 1of 17
 
0123456789();:
Nasopharyngeal carcinoma (NPC) is endemic to southern China, southeast Asia and north Africa, with age- standardized rates of 4–25 cases per 100,000 individ-uals in these regions according to GLOBOCAN
, which are 50–100 times greater than the rates in other parts of the world. The incidence and mortality from NPC have declined over the past 30 years in some endemic areas, such as Hong Kong, Singapore and Taiwan
35
. For exam-ple, NPC mortality in men decreased by 31.3% in Hong Kong from 2002 to 2012
5
. However, in other endemic areas, such as some southern provinces of mainland China, the incidence of NPC has remained static over the past two decades
6
. The trend of reduced NPC inci-dence and mortality observed in some regions has been attributed to multiple factors, including changes in dietary patterns, socioeconomic status and improved management of the disease
5
.This Review is a comprehensive, interdisciplinary overview of the key research findings regarding NPC pathogenesis, treatment, screening and biomarker devel-opment that have led to improvement in the treatment outcomes of patients with NPC. Furthermore, we pro- vide the historical context to illustrate the effect of these advances on the current management of NPC. Finally, we also highlight the challenges and controversies in preclinical and clinical research in NPC, with the hope of generating insights for future investigation.
NPC pathogenesis
NPC is classified into three subtypes: keratinizing squamous cell carcinoma, non- keratinizing squamous cell carcinoma, and undifferentiated or poorly differ-entiated carcinoma
7
. The non- keratinizing subtype of NPC accounts for >95% of cancers in endemic areas, whereas it accounts for 75% of NPC cases in the United States
8
; this unique geographical distribution is attrib-uted aetiologically to both genetic and environmental factors
912
. Linkage and genome- wide association studies in high- risk southern Chinese populations have revealed that certain
HLA
 haplotypes and multiple germline var-iants in the region encoding MHC class I molecules, on chromosome 6p21, are associated with genetic sus-ceptibility to NPC
. Infection with EPV is ubiquitous in non- keratinizing NPC and has a crucial pathogenic role. Two non- synonymous
BALF2
 variants in the EBV genome are associated with high risk of developing NPC in southern China and these variants have been implicated in up to 83% of the overall risk of NPC in this region
. The interplay of unique genetic factors and EBV variants might contribute to the increased
Nasopharyngeal carcinoma: an evolving paradigm
Kenneth C. W. Wong 
1
, Edwin P. Hui 
1
, Kwok- Wai Lo 
2
, Wai Kei Jacky Lam 
3
, David Johnson
1
, Lili Li 
1
, Qian Tao 
1
, Kwan Chee Allen Chan
3
, Ka- Fai To
2
, Ann D. King 
4
, Brigette B. Y. Ma 
1
 
 and Anthony T. C. Chan 
1
 
Abstract | The past three decades have borne witness to many advances in the understanding of the molecular biology and treatment of nasopharyngeal carcinoma (NPC), an Epstein–Barr virus (EBV)- associated cancer endemic to southern China, southeast Asia and north Africa. In this Review, we provide a comprehensive, interdisciplinary overview of key research findings regarding NPC pathogenesis, treatment, screening and biomarker development. We describe how technological advances have led to the advent of proton therapy and other contemporary radiotherapy approaches, and emphasize the relentless efforts to identify the optimal sequencing of chemotherapy with radiotherapy through decades of clinical trials. Basic research into the pathogenic role of EBV and the genomic, epigenomic and immune landscape of NPC has laid the foundations of translational research. The latter, in turn, has led to the development of new biomarkers and therapeutic targets and of improved approaches for individualizing immunotherapy and targeted therapies for patients with NPC. We provide historical context to illustrate the effect of these advances on treatment outcomes at present. We describe current preclinical and clinical challenges and controversies in the hope of providing insights for future investigation.
1
State Key Laboratory of Translational Oncology, Sir YK Pao Centre for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR.
2
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR.
3
Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR.
4
Department of Diagnostic Imaging and Interventional Radiology, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR.
REVIEWS
NATURE REVIEWS
|
 CLINICAL ONCOLOGY
 
0123456789();:
risk of persistent infection and clonal expansion of EBV- infected epithelial cells owing to their influence on the host immune response and/or viral lytic reactivation. EBV has a tropism for both B cells and epithelial cells, although the inability to detect EBV genomes or viral proteins in non- malignant nasopharyngeal epithelial cells suggests that several acquired genetic alterations and cellular factors are essential for the maintenance of per-sistent latent infection
. Decades of research have led to the development of a hypothetical model of NPC patho-genesis, whereby genetically susceptible nasopharyngeal epithelial cells undergo malignant transformation upon acquisition of persistent latent EBV infection and expres-sion of various viral oncogenic proteins and non- coding RNAs, which enable cellular transformation and clonal expansion
(FIG. 1)
. The subsequent accumulation of multiple genetic and epigenetic events culminates in an invasive phenotype promoting NPC progression
. Early driver events in NPC carcinogenesis include dys-regulation of the cyclin D1–Rb pathway (for example, through
CCND1
 overexpression or homozygous dele-tion of
CDKN2A
) and inactivation of tumour suppressor genes (such as
TGFBR2
), and contribute to tumour ini-tiation by facilitating persistent latent EBV infection
1821
. The episomal EBV genome and expression of Latency II genes, which encode several viral oncoproteins (EBNA1, LMP-1 and LMP-2A) and non- coding RNAs (Epstein–Barr virus- encoded small RNAs (EBERs) and microRNA- BARTs), promote global epigenetic changes in the host genome, ultimately affecting various cancer hallmarks, including unlimited cell growth, apopto-sis resistance, immune evasion, tumour- promoting inflammation and genome instability 
. Indeed, EBV- driven global cellular DNA methylation, which causes genome- wide epigenetic silencing of multiple tumour suppressor genes (such as
TET1, CDKN2A, RASSF1, RASAL1, PCDH10, ZNF382, DLEC1
 and
ZBTB28
), has been well documented
2226
, suggesting a key role for EBV- induced epigenetic modifications in the molecular pathogenesis of NPC
(TABLE 1)
.Whole- exome sequencing and whole- genome sequencing studies have shown that dysregulation of the NF- κB signalling pathway, caused by various somatic alterations in genes encoding members of this pathway and/or by overexpression of the EBV- encoded protein LMP-1, is the predominant oncogenic driver of NPC
18,2729
. Moreover, whole- exome and whole- genome sequencing studies have revealed that immune eva-sion in NPC is usually driven by somatic alterations impairing antigen- presentation mechanisms (such as inactivating mutations in
NLRC5
 and
HLA
)
 or by the overexpression of BNLF2a, an EBV- encoded inhibitor of antigen peptide transporters 1 and 2 (TAP1 and TAP2)
. Cellular–viral interactions affecting multiple cancer hall-marks can promote NPC progression. Despite the low incidence of
TP53
 mutations in NPC (5.3% to 9.5%) relative to other head and neck cancers (~85%),
TP53
 mutations are consistently detected more frequently in recurrent and/or metastatic (R/M) NPC than in primary NPC (15.2% versus 6.4%), suggesting a potential role in cancer progression
. Whole- exome sequencing studies revealed the frequent somatic alterations of
TGFBR2
 in NPC primary tumours and tumour- derived cell lines
. These new findings support a driver role of the TGFβ–Smad signalling pathway in NPC tumorigen-esis. Other important acquired genetic events include alterations in genes regulating epigenetic modifications or chromatin remodelling
(TABLE 1)
, cell- cycle control, and the PI3K–AKT and MAPK pathways
. In the past few years, advances in single- cell RNA transcrip-tomic profiling have provided insights into the intratu-moural heterogeneity of the immune cells in the tumour microenvironment
. Together, these genomic studies have presented clinically relevant biomarkers and novel therapeutic targets in NPC.Despite the findings from extensive whole- genome sequencing studies, CpG methylation- related gene silencing remains the most common genetic alteration found in NPC
. Multiple epigenomic studies have led to the identification of a series of cancer genes (either novel or well established) frequently methylated in NPC. These genes include regulators of cell signalling and epigenetic modifiers
(TABLE 1)
, suggesting that viral- induced epige-netic abnormalities have a key role in the pathogenesis of NPC.
Screening for NPC
In endemic areas for NPC, such as Hong Kong, >50% of patients present with advanced- stage disease
 (stage III–IV disease according to the seventh edition of the American Joint Committee on Cancer (AJCC) classi-fication (Supplementary Table 1). Early stage NPC is highly curable, and EBV screening in endemic popula-tions could improve the stage distribution of NPC and reduce cancer- related mortality. Successive generations of screening approaches based on the detection of anti-bodies against EBV in serum, coupled with nasoendos-copy in high- risk families or populations, have been tested in cohort studies
3641
. The diagnostic performance of these serological tests is highly variable depending on the assay and methods used, with sensitivities between 40.9% and 92.7%
. The results of a population- based, cluster- randomized screening trial (PRO- NPC-001) combining serological detection of anti- VCA and anti- EBNA1 antibodies with indirect mirror examina-tion of the nasopharnyx and/or lymphatic palpation
Key points
Basic research studies elucidating the genomic, epigenomic and immune landscapes of nasopharyngeal cancer (NPC) have laid the foundation for translational research to develop new therapeutic targets and biomarkers for this malignancy.Chemoradiotherapy is the treatment backbone for locoregionally advanced NPC; induction chemotherapy followed by chemoradiotherapy is the new standard- of- care therapy in this disease setting.In the past decades, advances in radiotherapy, including arc- based intensity- modulated approaches, proton therapy, adaptive radiotherapy planning and incorporation of artificial intelligence, have contributed to the improvements in treatment outcomes.Immunotherapy has become an important treatment modality that is being intensively investigated in different clinical settings, either as monotherapy or in combination with other agents.Plasma EBV DNA has enabled risk stratification and real- time assessment of response to therapy; multiple prospective studies are evaluating its role in guiding therapy.
www.nature.com/nrclinonc
REVIEWS
5
 
0123456789();:
among 70,296 participants from southern China were reported in 2019
. The study did not meet its primary end point of reduction of NPC- related mortality in the screening group (
n
 = 29,413) versus the control group (
n
 = 50,636); however, the percentage of patients with stage I–II NPC was higher in the screening group than in the control group (79% versus 20.6%).Our group has used real- time quantitative PCR for the detection of circulating EBV DNA in plasma from patients with NPC
. The utility of this approach in NPC screening has been evaluated in a cohort of 20,174 asymptomatic individuals
. Those with positive test results subsequently underwent nasoendoscopy and magnetic resonance imaging (MRI). In compari-son with a historical control cohort
, individuals who underwent screening were more likely to have stage I–II disease at diagnosis (71% versus 20%) and had higher 3- year progression- free survival (PFS; 97% versus 70%,
 
<
 0.001)
. In a cost- effectiveness analysis published in 2020, the costs for plasma EBV DNA and serology testing were estimated to be US$20.36 and $16.50, respectively 
, although the latter estimate does not include the cost for indirect mirror examination of the nasopharynx and lymphatic palpation
. Importantly, the percentage of individuals requiring follow- up endo-scopic examination were 1.5% and 3.9% among those screened using plasma EBV DNA
 and serology 
, respectively, and the positive predictive values of the two approaches were 11.1% and 4.8%. Data from subsequent studies of next- generation screening approaches based on the analysis of fragment size and methylation patterns in EBV DNA can improve the specificity, with positive predictive values of 19.6% and 35.1%, respectively 
.MRI has long been used to stage head and neck carci-nomas and also has a role complementary to that of endo-scopic examination in the detection of early stage NPC
.
Nonmalignantnasopharyngealepithelium
Early genetic lesions
Pre-invasive lesions(dysplaxia, NPIs)Invasive carcinomaDistantmetastasis
 LOH of 3p and 9p
 
CDKN2A
,
TGFBR2
and
RASSF1
A inactivation
Clonal expansion of EBV-infected cellsActivation of cancer hallmarksEBV latent infectionAcquired gene mutations
 Somatic gene alterations in NF-
 
B pathways:
TRAF3
,
CLYD
,
NFKBIA
 Mutations in MHC class I genes:
NLRC5
,
HLA-A
,
HLA-B
,
HLA-C
 Mutations in chromatin remodelling processes:
KMT2C
,
KMT2D
,
BAP1
 Mutations in PI3K/MAPK pathways:
PTEN
,
PIK3CA
,
FGFR3
 
TP53
and
RAS
gene mutations
Genetic susceptibility (for example, HLA haplocytes, NPC-associated SNPs)Tumour formationEBV-driven genome instability and hypermethylationTumour progression
ChemicalcarcinogensInfectiveEBV vironEpisomalEBV genome
Tumour-infiltrating
lymphocyte
 Expression of viral oncoproteins (EBNA1, LMP1, LMP2, BNLF2a, BARF1)
 Expression of EBV non-coding RNAs (EBERs, microRNA-BARTs, BART long non-coding RNAs
Fig. 1 | 
Hypothetical model of NPC pathogenesis
.
 Exposure to environmental carcinogens induces various genetic lesions (such as deletions in chromosomes 3p and 9p) and subsequent inactivation of key tumour suppressor genes (such as
CDKN2A
 and
TGFBR2
) that predispose to Epstein–Barr virus (EBV) infection and transformation of nasopharyngeal epithelial cells. In nasopharyngeal epithelial cells persistently infected with EBV, the presence of episomal viral genomes and expression of Latency II viral proteins (EBNA1, LMP-1 and LMP-2) and non- coding RNAs (Epstein–Barr virus- encoded small RNAs (EBERs), microRNA- BARTs and BART long non- coding RNAs) promote genome instability, induce global DNA methylation and activate virtually all cancer hallmarks. Clonal expansion of EBV- transformed nasopharyngeal epithelial cells leads to the accumulation of multiple genetic and epigenetic events driving nasopharyngeal carcinoma (NPC) progression. The convergence of somatic genomic alterations (such as mutations in the pro- inflammatory NF- kB pathway and in components of antigen presentation machinery) and EBV latent gene expression (for example, of LMP-1 and BNLF2a) modulates the tumour microenvironment and immune escape. Other acquired genetic changes (including alterations of
TP53
, genes involved in chromatin remodelling and components of the PI3K–MAPK pathway) contribute to tumour progression, occurrence of local recurrences and distant metastasis. HLA, human leukocyte antigen; LOH, loss of heterozygosity; MHC, major histocompatibility complex; NPI, nasopharyngeal inlet; SNP, small nucleotide polymorphism.
NATURE REVIEWS
|
 CLINICAL ONCOLOGY
REVIEWS
5
 
0123456789();:
An MRI- based grading system developed in 2011 (and updated in 2020
) enables very sensitive detection of NPC, including those cancers hidden from endoscopic  view in the pharyngeal recess, roof and submucosa, or masked by benign hyperplasia. In the first prospective study that compared the diagnostic performance of MRI and endoscopic examination, 10% of all NPCs diagnosed in a group of individuals without (69%) and with NPC (31%) were detected only by MRI
. In a second prospective study involving a group of asymp-tomatic individuals screened using plasma EBV DNA, this figure rose to 17.6%
. Moreover, among 275 partic-ipants, three had slow- growing early stage cancers that were observed on MRI around 3 years before they were endoscopically visible
. In future, the successful imple-mentation of NPC screening in any endemic population will depend on efforts to improve the performance (for example, using next- generation sequencing platforms for plasma EBV DNA analysis
) and cost- effectiveness of screening tests, and on the availability of imaging tools to localize subclinical lesions.
Management of locoregionally advanced NPC
Historical overview.
NPC is a highly radiosensitive and chemosensitive tumour type. Owing to its challenging anatomical location, radiotherapy is the mainstay of treat-ment for non- metastatic disease (that is, any T, any N, M0 disease). Chemotherapy is generally considered except for patients with stage I disease ((T1N0, accord-ing to the eighth edition of the AJCC classification). Nowadays, nearly all patients with stage I–II NPC are cured with intensity- modulated radiotherapy (IMRT) with or without chemotherapy: at 5 years, the esti-mated overall survival (OS) for stage I and II NPC is 98% and 92%, respectively, locoregional failure- free sur- vival (FFS) is 98% and 94%, and distant FFS is 98% and 91%
. Historically, patients with stage III–IVA disease had poor prognosis owing to the high incidence of dis-tant metastasis following conventional two- dimensional (2D) radiotherapy alone, and 5- year OS and PFS were 58.6% and 52.1%, respectively, according to a report analysing studies from the late 1990s
. Two important changes in the treatment paradigm emerged in the early 2000s, with the addition of concurrent chemotherapy to radiotherapy 
 and a gradual switch from conven-tional radiotherapy techniques to IMRT
. The land-mark MAC- NPC meta- analysis showed that concurrent chemoradiotherapy increases 5- year OS and PFS to 70.4% and 61.1%, respectively 
. In the current decade, induction chemotherapy has received renewed interest, with several trials demonstrating an OS benefit when added to concurrent chemoradiotherapy. As a result, the outcomes of patients with locoregionally advanced NPC have improved over the past three decades
(FIG. 2)
.
Concurrent chemoradiotherapy.
Concurrent chemora-diotherapy is currently the therapeutic backbone in the standard management of patients with non- metastatic stage III–IV NPC. The landmark INT-0099 study was the first phase III trial conducted in a non- endemic region
Table 1 | 
Key epigenetic drivers in NPC
GeneChromosomal locationFunctionAlterations in NPCFrequency of alteration
DNA methylation
DNMT1
19p13.2DNA methyltransferaseOverexpression
~97%
TET1
10q21.35- methylcytosine hydroxylase; active DNA demethylationMethylation and mutation
Methylation ~55% and mutation ~4%
IDH2
15q26.1Isocitrate dehydrogenaseOverexpression
Not available
Histone modification
KMT2C
7q36.1Histone H3K4 methyltransferaseMutation
~11–18%
EZH2
7q36.1Histone H3K27 methyltransferaseOverexpression
253255
~72%
EED
11q14.2PRC2 subunit of PRC2/EEDEZH2 complex; transcriptional repressionOverexpression
~88%
BMI1
10p12.2PRC1 subunit of polycomb complex; transcriptional repressionOverexpression
~38%
Chromatin remodelling
 ARID1A
1p36.11Component of SWI/SNF complexes; transcriptional activation and repressionMutation
~10%
BRD7
16q12.1PBAF- specific subunit of SWI/SNF complexes; transcriptional co- activator or co- repressorMethylation
>
90%
PRDM5
4q27DNA- binding transcription factor; transcriptional repressionMethylation
~93%
EP300
22q13.2Histone acetyltransferaseMutation
~5%
HELLS
10q23.33SNF2- like helicase; chromatin binding and helicase activityOverexpression
~67%
NPC, nasopharyngeal carcinoma.
www.nature.com/nrclinonc
REVIEWS
5
5
5
5
5
5
5
5
5
5
5
5
5
5

Reward Your Curiosity

Everything you want to read.
Anytime. Anywhere. Any device.
No Commitment. Cancel anytime.
576648e32a3d8b82ca71961b7a986505