Original Article Analysis of Plasma Epstein Barr Virus DNA to Screen for Nasopharyngeal Cancer

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1 Original Article Analysis of Plasma Epstein Barr Virus DNA to Screen for Nasopharyngeal Cancer K.C. Allen Chan, F.R.C.P.A., John K.S. Woo, F.R.C.S., Ann King, F.R.C.R., Benny C.Y. Zee, Ph.D., W.K. Jacky Lam, F.R.C.S., Stephen L. Chan, F.R.C.P., Sam W.I. Chu, B.Sc., Constance Mak, B.S.N., Irene O.L. Tse, B.N., Samantha Y.M. Leung, B.N., Gloria Chan, R.N., Edwin P. Hui, F.R.C.P., Brigette B.Y. Ma, M.D., Rossa W.K. Chiu, F.R.C.P.A., Sing-Fai Leung, F.R.C.R., Andrew C. van Hasselt, F.R.C.S., Anthony T.C. Chan, F.R.C.P., and Y.M. Dennis Lo, F.R.S. N Engl J Med Volume 377(6): August 10, 2017

2 ΕΙΣΑΓΩΓΗ Ο καρκίνος του ρινοφάρυγγα (ΡΚ) συχνός την ΝΑ Ασία Σε µεσήλικες άνδρες, η επίπτωση σε ενδηµικές περιοχές 35 / άτοµα Παράγοντες κινδύνου: Οικογενειακό ιστορικό Παστά ψάρια Κάπνισµα

3 ΕΙΣΑΓΩΓΗ Η έκταση του ΡΚ κατά τη διάγνωση ο σηµαντικότερος παράγων επιβίωσης Η 5-ετής επιβίωση σταδιο Ι 95% σταδιοiv 60% Σχετικώς ασυµπτωµατικό Το 80%κατά τη διάγνωση µε τοπικά προχωρηµένη νόσο ή µεταστάσεις Η αναζήτηση ασθενών σε αρχικό στάδιο µε screeningθα µπορούσε να επηρεάσει την επιβίωση

4 ΕΙΣΑΓΩΓΗ Παθογενετική συσχέτιση µε τον Epstein Barr virus (EBV) Η αναζήτηση anti-ebv IgAχαµηλή ευαισθησία και ειδικότητα Παλαιότερη µελέτη είχε δείξει ότι οι ασυµπτωµατικοί ασθενείς µε αρχικού σταδίου ΡΚ είχαν µονιµη παρουσία EBV DNAστο πλάσµα ενώ οι άλλοι όχι (συχνά παροδική). Το EBV DNAστο πλάσµα περιλαµβάνει βραχέα τµήµατα DNA fragments (<181 bp)που απελευθερώνονται από τα νεοπλασµατικά κύτταρα και όχι ιικά σωµατίδια Κάθε νεο-κύτταρο περιέχει 50 copiesτου EBV γωνιδιώµατος.

5 ΕΙΣΑΓΩΓΗ Production of virion DNA involves a viral DNApolymerase that can be inhibited by nucleosideanalogues such as acyclovir and ganciclovir. Incontrast, viral DNA in latently infected cells persistsas a nuclear plasmid or episomethat isreplicated by host-cell DNA polymerases in synchronywith the cell cycle such that after mitosis,daughter cells also carry viral DNA. In tumors,virus is predominantly latent and cellular proliferationresults in the perpetuation of nuclearplasmids. The addition of antiviral agentsthat inhibit the EBV DNA polymerase and blockthe production of virions would not be expectedto alter either measurements of EBV DNA inplasma or the natural history of an establishedtumor.

6 ΕΙΣΑΓΩΓΗ Viral-load measurements have proved usefulin the management of hepatitis B Hepatitis C Human immunodeficiency virus Cytomegalovirus

7 ΕΙΣΑΓΩΓΗ Most existing tumor markers that are used forcancer screening are proteins or glycoproteins(e.g., PSA, a1 Fet). Nasopharyngeal carcinomaas a model to show the potential application of analysis of circulating DNA for cancer screening. A fundamental question is whether asmall tumor would release sufficient amounts oftumor DNA into the circulation to allow sensitivedetection of the cancer-associated changes.

8 ΕΙΣΑΓΩΓΗ In healthy persons,circulating cell-free DNA is composed of DNA originating from normal cells. In early-stage cancer, only a small fraction of cell-free DNA is derived from tumor. Αnalysis of circulating DNA derivedfrom cancer cells, which is frequently known as a liquid biopsy is being evaluated as a tool in the care of patients with cancer Sensitive screening for cancer-associated mutationsin turn yields false positive results, because with increasing age, people in whom cancer will never develop during their lifetimes nonetheless acquire cancer associated mutations.

9 ΕΙΣΑΓΩΓΗ A wide range of cancer-associated changes, including point mutations, copy number aberrations, and alterations in DNA methylation, have been detected in the plasma of patients with cancer, the clinical applicationsof analysis of circulating tumor DNA have thusfar been focused primarily on guiding treatment selection and detection of residual disease Much less information on the use ofanalysis of circulating DNA to screen for early cancers Challenges are assay sensitivity and specificity

10 Η ΜΕΛΕΤΗ Προοπτική µελέτη ασυµπτωµατικώνατόµων Κινέζοι άνδρες ετών, Hong Kong 147 Public health education sessionsjuly 2013-February 2016 Γνωστό ότι είναι σε αυξηµένο κίνδυνο ΣΚΟΠΟΣ EBV DNA στο πλάσµα για screeningγια ΡΚ Είναι κατάλληλο για διάγνωση σε πρώιµο στάδιο?

11 20 ml αίµα ΑΣΘΕΝΕΙΣ & ΜΕΘΟ ΟΙ Ελεγχος για EBV DNA real-time polymerase-chain-reaction (PCR) assaythat targeted the Bam HI-W fragment of the EBVgenome The lowerdetection limit : 20 EBV genomesper ml Όσοι ήταν θετικοί επανάληψη σε 4 εβδοµάδες και όσοι παρέµεναν θετικοί έλεγχος µε οπισθία ρινοσκοπία και MRI Κάθε χρόνο επικοινωνία τηλεφωνικώς 19,626 (97.4%) εάν διεγνώσιη ΡΚ ιάµεση παρακολούθηση 22 µήνες (όρια, 12-44). March 31, 2017, the totalfollow-up of the cohort was 40,909 person-years.

12 Ιστορικό Καρκίνου ΑΣΘΕΝΕΙΣ &ΜΕΘΟ ΟΙ Αυτοάνοσου νοσήµατος Κορτικοθεραπευόµενοι Ανοσοκατεσταλµένοι ΑΠΟΚΛΕΙΣΜΟΣ Λόγω πιθανού ιικού πολλαπλασιασµού

13 ENROLLMENT, SCREENING OF EPSTEIN BARR VIRUS DNA IN PLASMA, AND CONFIRMATION OF NASOPHARYNGEAL CARCINOMA BY MEANS OF NASAL ENDOSCOPY AND MAGNETIC RESONANCE IMAGING IN THE PARTICIPANTS Chan KCA et al. N Engl J Med 2017;377: ,349 Participants from 147 community health education sessions were enrolled 20,174 Were eligible 175 Were excluded 120 Had two enrollment attempts 9 Had concurrent cancers 31 Were receiving systemic glucocorticoid or other immunosuppressive agents 15 Had an autoimmune disease 1112 Had detectable Epstein Barr virus DNA in plasma at baseline 309 Had detectable Epstein Barr virus DNA in plasma at baseline and at follow-up 300 Underwent nasal endoscopy 275 Underwent MRI 25 Did not undergo MRI 12 Declined to undergo MRI 11 Had metal implants 2 Had impaired renal function 9 Declined further evaluation with nasal endoscopy or MRI 34 Had confirmed nasopharyngeal carcinoma 1 Had advanced nasopharyngeal carcinoma 32 mo later

14 ΑΠΟΤΕΛΕΣΜΑΤΑ 1112 θετικοί (5.5%) 309 (1.5%από όλους &27.8%από τους αρχικώς θετικούς) µόνιµα EBVDNA Οι 300οπισθία ρινοσκοπία και 275 και MRI 34/ 309 (11.0%) ΡΚ. 9 δεν θέλησαν επανάληψη και ο 1 ΡΚ 32 αργότερα Μόνο 1χωρίς EBV DNAανέπτυξεΡΚ 1 χρόνο αργότερα. Πολύ χαµηλό για ετήσια επίπτωση

15 FINDINGS ON NASAL ENDOSCOPY AND AXIAL T 1 -WEIGHTED MRI OF A 48-YEAR-OLD MAN WITH A SMALL NASOPHARYNGEAL CARCINOMA IN THE RIGHT PHARYNGEAL RECESS (STAGE T1). Chan KCA et al. N Engl J Med 2017;377:

16 ΑΠΟΤΕΛΕΣΜΑΤΑ Με επίπτωση 35 cases per100,000 persons in the target age groupστην cohort of 20,174 ανεµένοντο 7 participants/ χρόνο. Tα 34ανεµένονταν σε 5 χρόνια. Θα βρισκόντουσαν τα επόµενα χρόνια σε πιο προχωρηµένο στάδιο Σ αυτο συνηγορεί και µόνο 1 τον επόµενο χρόνο

17 SENSITIVITY AND SPECIFICITY OF THE TWO-STAGE SCREENING PROTOCOL FOR THE DETECTION OF NASOPHARYNGEAL CARCINOMA* Finding Screen-Positive (N = 308) Screen- Negative (N = 19,865) Confirmed nasopharyngeal carcinoma by the screening 34 1 protocol or nasopharyngeal carcinoma reported to have developed within 1 yr no. No nasopharyngeal carcinoma within 1 yr after screening no ,864 Sensitivity % (95% CI) 97.1 ( ) Specificity % (95% CI) 98.6 ( ) Positive predictive value % (95% CI) 11.0 ( ) Negative predictive value % (95% CI) ( ) Proportion of stage I/II disease in the 34 cases of nasopharyngeal carcinoma identified by screening % (95% CI) 70.6 ( ) * Screen-positive is defined as persistently positive for plasma EBV DNA at baseline and at follow-up. Screen-negative is defined as negative for plasma EBV DNA either at baseline or at follow-up. The participant who had declined further investigation but in whom advanced nasopharyngeal carcinoma developed 32 months after screening is not included in this number. Chan KCA et al. N Engl J Med 2017;377:

18 ΑΠΟΤΕΛΕΣΜΑΤΑ Χαµηλή θετική προγνωστική αξία έχουν όλα τα cancerscreening σε ασυµπτωµατικό πληθυσµό. Σε Κορεατική µελέτη screened 45,855 για ΗΚΚ, µε alphafetoprotein:1.66%. Το 3%είναι το όριο για να βοηθά Το 11% της µελέτης είναι πολύ. Η ρινοσκόπηση ασφαλής, γρήγορη και φθηνή σε σχέση µε επιβεβαίωση άλλων καρκίνων.

19 STAGE DISTRIBUTION AMONG THE PARTICIPANTS WITH NASOPHARYNGEAL CARCINOMA IDENTIFIED BY SCREENING Stage Distribution of Patients with Nasopharyngeal Carcinoma Pe ercentage of Patients in Different Stages Stage I Stage II Stage III Stage IV Patients Identified by Screening All Patients with Nasopharyngeal Carcinoma in Hong Kong in 2013 Chan KCA et al. N Engl J Med 2017;377:

20 ΑΠΟΤΕΛΕΣΜΑΤΑ 16/ 34 (47%) stage Idisease (5 to 7% in historicalcohorts) Stage I or II diseaseσε σχέση µε historical cohort (71% vs. 20%, P<0.001 by the chi-square test) Between 2006 and 2010,120 /2671µε ΡΚ (4.5%) stage I. Intensity-modulatedradiotherapyαντί more extensive radiotherapy and chemotherapy 3-yearprogression-free survival (97% vs. 70%;hazard ratio, 0.10; 95% confidence interval, 0.05to 0.18).

21 PROGRESSION-FREE SURVIVAL AMONG THE PARTICIPANTS WITH NASOPHARYNGEAL CARCINOMA IDENTIFIED BY SCREENING Progression-free Survival 100 Probability of Survival (% %) No. at Risk Patients identified by screening Patients in historical cohort Patients identified by screening Patients in historical cohort Hazard ratio, 0.10 (95% CI, ) Months since Start of Treatment Chan KCA et al. N Engl J Med 2017;377:

22 ΣΥΖΗΤΗΣΗ Το κόστος EBV DNA analysis, endoscopic examination, and MRI were $30, $80 &$1,000αντιστοίχως. Για 1 ασθενή, 593 screened µε κόστος $28,600. Οικονοµικώς συµφέρον αφού εντοπίζοπνται σε πρώιµο στάδιο Για ενδηµικές χώρες Α retrospectivesurvey of unselected patients in whom EBV DNAwas detected in plasma samples at Johns HopkinsHospital, approximately 1% had nasopharyngealcarcinoma high-risk populations,or high-risk persons

23 ΣΥΜΠΕΡΑΣΜΑΤΑ Circulating cell-free Epstein Barr virus (EBV) DNA is a biomarker for nasopharyngealcarcinomafor early detection,with a sensitivity of 96% and a specificityof 93%. in the right,population Like cervical cytologic testing or testing for humanpapillomavirus in the cervix for early detectionof cervical cancer,plasma EBV DNA screeningmay profoundly change the natural historyof nasopharyngeal carcinoma.

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25 Chan KCA et al. N Engl J Med 2017;377: Characteristic Age yr Median IQR DEMOGRAPHIC CHARACTERISTICS OF THE STUDY PARTICIPANTS - I Age distribution no. (%) yr yr yr yr yr All Eligible Participants (N = 20,174) ,901 (19.3) 3,972 (19.7) 5,295 (26.2) 4,680 (23.2) 2,326 (11.5) Plasma EBV DNA Positive at Baseline (N = 1112) (15.5) 198 (17.8) 268 (24.1) 288 (25.9) 186 (16.7) Plasma EBV DNA Positive at Baseline and at Followup (N = 309) (16.2) 60 (19.4) 71 (23.0) 79 (25.6) 49 (15.9) Confirmed Nasopharynge al Carcinoma (N = 34) (26.5) 5 (14.7) 10 (29.4) 9 (26.5) 1 (2.9) Historical Cohort (N = 1278) (30.7) 312 (24.4) 240 (18.8) 221 (17.3) 113 (8.8) yr 2,326 (11.5) 186 (16.7) 49 (15.9) 1 (2.9) 113 (8.8) Smoking status no. (%) Never smoked Current or recent smoker Stopped smoking for >1 yr 12,665 (62.8) 4,045 (20.1) 3,463 (17.2) 634 (57.0) 296 (26.6) 182 (16.4) 165 (53.4) 93 (30.1) 51 (16.5) 25 (73.5) 8 (23.5) 1 (2.9)

26 Chan KCA et al. N Engl J Med 2017;377: Characteristic Drinking status no. (%) Nondrinker Drinker DEMOGRAPHIC CHARACTERISTICS OF THE STUDY PARTICIPANTS - II Units of alcohol consumed/wk (no, %) < >10 History of nasopharyngeal carcinoma in first-degree relative no. (%) No Yes In parents In siblings In children All Eligible Participants (N = 20,174) 7,071 (35.1) 13,103 (64.9) 7,594 (37.6) 4,055 (20.1) 892 (4.4) 562 (2.8) 19,171 (95.0) 1,003 (5.0) 759 (3.8) 250 (1.2) 2 (<0.1) Plasma EBV DNA Positive at Baseline (N = 1112) Plasma EBV DNA Positive at Baseline and at Followup (N = 309) (N = 1112) up 381 (34.3) 731 (65.7) 427 (38.4) 213 (19.2) 55 (4.9) 36 (3.2) 1010 (90.8) 102 (9.2) 66 (5.9) 40 (3.6) (37.5) 193 (62.5) 106 (34.3) 63 (20.4) 13 (4.2) 11 (3.6) 280 (90.6) 29 (9.4) 18 (5.8) 11 (3.6) 0 Confirmed Nasopharynge al Carcinoma (N = 34) 17 (50.0) 17 (50.0) 8 (23.5) 6 (17.6) 2 (5.9) 1 (2.9) 26 (76.5) 8 (23.5) 4 (11.8) 4 (11.8) 0 Historical Cohort (N = 1278)

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