E-Learning Prognostic and Predictive Biomarkers in Head & Neck … · A prognostic biomarker indicates the likely course of the disease in untreated patients (or regardless of treatment)

PROGNOSTIC AND PREDICTIVE BIOMARKERS IN HEAD & NECK CANCER

Lisa Licitra, MD and Salvatore Alfieri, MD

Fondazione IRCCS-Istituto Nazionale dei Tumori, Milan, Italy

Stage I-II (T1-T2 N0): Early disease

Surgery or radiotherapy (larynx, hypopharynx, oropharynx, oral cavity1)

Radiotherapy2 (nasopharynx)

Stage III-IV (T3-T4 and/or N+): Locally advanced disease

Concomitant chemo3/bio4-radiotherapy (C or B-RT)

(larynx/hypopharynx5, oropharynx, oral cavity6, nasopharynx7)

Induction chemotherapy (ICT) followed by radiotherapy +/- chemotherapy is a

real alternative therapy (vs. C or B-RT) in larynx/hypopharynx in the organ-

preservation strategy; in all other subsites ICT may be an option in clinical trials

Stage IV (Any T, Any N, M1): Recurrent or metastatic disease deemed not eligible

for salvage surgery or radiotherapy

Palliative chemotherapy or Best Supportive Care

SITE AND STAGE-DRIVEN

TREATMENT IN HEAD AND NECK CANCER

1.In oral cavity, if transoral resection without sequelae is feasible, surgery is preferred versus radiotherapy

(e.g. brachitherapy); 2. +/- chemotherapy (in Stage II); 3.Chemotherapy with platinum-based schedules;

4. Bio-radiotherapy = cetuximab plus radiotherapy; 5. If a multimodality organ preservation strategy is feasible; if

not: surgery radiotherapy +/-chemotherapy; 6. If unresectable disease; 7. In nasopharynx only concomitant

chemio-radiotherapy;

A prognostic biomarker indicates the likely course of the disease in untreated

patients (or regardless of treatment)

A predictive biomarker identifies subpopulations of patients, who are most likely to

respond to a given therapy

PROGNOSTIC AND PREDICTIVE

BIOMARKERS

BIOMARKERS PROGNOSTIC PREDICTIVE

EBVin endemic nasopharyngeal cancers (NPC)

HPV

PET imagingpost-treatment

Hypoxia

EGFR**

TP53 gene mutation

Gene-expression profiles

Immune checkpoint-related

Validated Not Validated Potential

**Potential predictive factor for accelerated radiotherapy

BIOMARKERS IN HEAD AND

NECK CANCER

A close association between

EBV and NPC has been

established

The prognostic role of pre- or

post-treatment EBV DNA is

validated only in endemic area

A comprehensive harmonisation

of quantitative plasma EBV DNA

assay is advocated

EPSTEIN-BARR VIRUS (EBV) DNA

OS and RFS lower in NPC pts with baseline

EBV DNA >1500 copies/ml

OS and RFS lower in NPC pts with detectable

post-treatment EBV DNA (1 week after radiotherapy)

Lin JC, et al. N Engl J Med 2004;350:2461-70 Copyright © (2004) Massachusetts Medical Society.

Reprinted with permission from Massachusetts Medical Society.

EPSTEIN-BARR VIRUS (EBV) DNA

OS and RFS lower in NPC pts with:

Baseline EBV-DNA > 4000 cps/ml + post-treatment EBV-DNA > 500 cps/ml

(post-treatment EBV-DNA detected 6-8 weeks after ending radiotherapy)

The cutoff of 4000 copies/ml for baseline EBV DNA was also identified as predictive value of

post-treatment distant failure in patients with early-stage (I-II) nasopharyngeal

carcinoma of undifferentiated type (Leung SF, Cancer 2003)

Chan ATC, et al. Journal of the National Cancer Institute, Vol. 94, No. 21, November 6, 2002, by permission of Oxford University Press

Bathia A and Burtness B, JCO September 8, 2015

HPV infection is very common worldwide, being the most frequent sexually

transmitted infection

About 20% of Squamous Cell Cancers of Head and Neck (SCCHN) are associated

with HPV infection, mainly oropharyngeal SCCHN (about 50%)

More than 130 HPV types are known and classified as low-risk or high-risk based

on their oncogenic potential

HPV16 is the most commonly found and is present in approximately 90% of

HPV-positive oropharyngeal cancers (OPC)

HUMAN PAPILLOMA VIRUS (HPV)

Integration of the virus into the

host genome

Disruption of E2 gene, a

transcriptional repressor of the

oncogenes E6 and E7

Increase of E6-E7 causes

alteration of:

- Normal cell growth

- Normal control DNA repair

- Apoptosis

by inactivation of two tumour

suppressor proteins, p53, and

retinoblastoma protein (Rb)

HPV: ONCOGENIC MECHANISM (1)

Kang H, et al. Nat Rev Clin Oncol 12, 11-26 (2015) Reprinted by permission from Macmillan Publishers Ltd, copyright 2014

HPV: ONCOGENIC MECHANISM (2)

Increase of E6-E7 causes:Blacklog of protein p16as part of a feedback loop attempting to applythe brakes to cell proliferation

Despite accumulation of p16, E7 overcomes its inhibitory effects via redundant pathways

Accumulation of p16:

- can serve to distinguish the two

different types of OSCCs, HPV-

induced and no HPV-related

- is a good surrogate marker of

HPV positivity (very high

sensitivity rate approching about

100% even if it does not warrant

of HPV-DNA integrated in the

host-genome

Reprinted from Gillison ML, et al. Semin Oncol 2004;31:744–54. Copyright 2004, with permission from Elsevier

HPV-induced OSCCs Tobacco/alcohol-induced OSCCs

HPV AND DIAGNOSIS

Westra WH, et al. Semin Diagn Pathol 2015:32;42–53

Bhatia A, Burtness B, J Clin Oncol 2015;33:3243–50

Schache AG, et al. Clin Cancer Res 2011

Klussmann JP, et al. Am J Pathol 2003

Adelstein DJ, et al. Head Neck 2009;31:1393-422

Images from: Smeets SJ, et al.

Int J Cancer 2007;121:2465–72

Copyright 2007 Wiley-Liss, Inc

Protein p16 can be detected by immunohistochemistry (IHC) with >70% nuclear and cytoplasmatic immunostaining

Protein p16 IHC (p16 IHC) is recommended as first diagnostic test but its low specificity rate (79%) does suggest that p16 IHC has to be followed by molecular analysis to test for

HPV DNA presence

In case of discordance (e.g. p16 positive/ISH negative result), quantitative polymerase chainreaction (qPCR) for both viral E6/E7 mRNA (RNA qPCR) or HPV DNA (DNA qPCR)

have also been advocated for use as confirmation

In-situ hybridisation of HPV (HPV ISH) is the gold standard and could be used either

simultaneously with the p16 IHC or as a second test for p16-positive cases

p16 NEGp16 POS

HPV-POS AND BETTER H&N

CAUSE-SPECIFIC SURVIVAL

STUDY N PTS SUBSITE % HPV TX HR

Gillison, 00 252 H&N 25 Surg and/or RT 0.40

Mellin, 01 34 Oroph 41 RT (100%) + Surg

(45%)

0.50

Schwartz, 01 254 H&N 15 Surg and/or RT 0.17

Lindel, 01 99 Oroph 14 RT + CT 0.35

Ritchie, 03 128 Oral + oroph 21 Surg and/or RT 0.30

Weinberger, 06 79 Oroph 61 RT (100%) + Surg

(40 %)

------

Licitra, 06 90 Oroph 19 Surg (100%) + RT

(66%)

0.26

HPV-POS AND BETTER H&N

CAUSE-SPECIFIC SURVIVAL

STUDY N PTS SUBSITE % HPV TX HR

Fahkry, 08

ECOG 2399

96 Oroph + lar 40 IndCT + CTRT 0.36

Lassen, 09

DAHANCA 05

135 H&N 22 RT (100%) 0.44

Rischin, 10

TROG 02.02

172 Oroph 57 CTRT 0.36

Posner, 11

TAX 324

111 Oroph 50 Ind + CTRT 0.20

Gillison, 12

RTOG 9003

190 Oroph 39 RT Nr p<0.001

Ang, 10

RTOG 0129

323 Oroph 64 CTRT 0.42

Lassen, 11

DAHANCA 6&7

769 H&N 769 RT 0.54

PROGNOSTIC RISK GROUPS IN

OPC: ANG CLASSIFICATION

Ang KK, et al. N Engl J Med 2010; 363:24-35, July 1, Copyright © (2010) Massachusetts Medical Society.

Reprinted with permission from Massachusetts Medical Society


OPC: O’SULLIVAN CLASSIFICATION

O’Sullivan B, et al. J Clin Oncol 31:543-550. Reprinted with permission, © 2013, American Society of Clinical Oncology. All rights reserved.

Either classifications may be used independently


HPV-POSITIVE OPC

Huang SH, et al. J Clin Oncol Feb 9, 2015,1-10, reprinted with permission. © 2015 American Society of Clinical Oncology. All rights reserved.

*

*TSG_OG = alterations in both TSG and OG

HPV-Positive:

Prevalence of

alterations in OG

HPV-Negative:

Prevalence of

alterations in TSG

*

Chung CH, et al. Ann Oncol (2015) 26 (6): 1216-1223. by permission of Oxford University Press and ESMO

HPV is able to distinguish two completely different groups of patients

either from a genetic and clinical point of view

HPV AND GENETICS (1)

Chung CH, et al. Ann Oncol (2015) 26 (6): 1216-1223. by permission of Oxford University Press and ESMO

HPV-Positive

HPV-Negative

HPV AND GENETICS (2)

HPV AND CLINICS

HPV-associated OPSCC HPV-negative OPSCC

Epidemiology/risk factors

1. Race White>Black White>Black

2. Age Between 4th and 6th decade Usually 7th decade

3. Sex (male:female) 8:1 3:1

4. Socioeconomic status Middle to higher Lower to middle

5. Smoking/alcohol history Never or minimal exposure Significant exposure

6. Marijuana use Strong association Not known

7. Early sexual debut Strong association Not known

8. Multiple lifetime sexual partners Strong association Not known

Clinical features

9. Tumour (T) stage Early tumour stage More advanced tumour stage

10. Nodal (N) stage More advanced nodal stage Early nodal stage

Outcomes in stage III/IVa,b

11. Distant metastatis risk Distant control rate:70–90% Distant control rate: 70–90%

12. Second primary (SP) risk Rate of SP:11% Rate of SP: 4.6%

13. Overall response to treatment >80% respond >50% respond

14. 2-year overall survival 95% (95%CI 87-100) 62% (95% CI 49-74)

Two distinct subtypes of oropharyngeal squamous cell carcinoma (OPSCC)

Illustrates the two distinct subtypes that differ by epidemiology, risk factors, clinical features and outcomes. CI, confidence interval

Redrawn from Marur S, et al. Current Opinion Oncology 2014;26:252–8

FDG-PET

Mainly small retrospective series are available about the role of post treatment FDG-PET in HNC

Kang H, et al. Nature Rev Clin Oncol 12, 11-26 (2015) Reprinted by permission from Macmillan Publishers Ltd: copyright 2014

Functional imaging with 18F-fluorodeoxyglucose PET (FDG-PET) improves the accuracy of HNC disease staging and treatment-response assessment

in comparison with CT or MRI alone

The timing of FDG-PET is not standardised yet but several studies suggested an optimal time interval of 12 weeks

BUT…

FDG-PET

PET-Neck Trial schema – Pragmatic non-inferiority trial

Courtesy of Prof Hisham Mehanna, presented at 2015 ASCO Annual Meeting

This phase III randomised controlled study (PET-NECK trial) showed non inferiority of FDG-PET guided active surveillance compared to Neck Dissection (ND) for locally advanced Head

and Neck Cancer patients treated with primary radical chemo-radiotherapy (CRT)

In clinic, FDG-PET performed after chemoradiotherapy or radiotherapy for HNC has a validated prognostic factor with very high Negative Predictive Value (NPV) of 95–100%

but low positive Predictive value (PPV) of 38-77%

Tumour hypoxia is a marker of poor prognosis in head and neck cancer

An in vitro model of tumour radiosensitivity was used to create a 10-gene

radiosensitivity index (RSI) and this index is a potential clinical prognostic marker

for locoregional control in patients with head and neck cancer treated with

concurrent chemoradiotherapy

Kasper Toustrup (DAHANCA1) identified a gene-expression classifier, consisting of

15 hypoxia-related genes, able to predict for hypoxic radiotherapy-induced

modifications in head and neck squamous cell cancer (Cancer Res, 2011). More

hypoxic tumours, found by this signature, had benefit in terms of DSS* and LRC**

when treated with nimorazole, which is a hypoxic modifier drug, versus placebo

(Radiother Oncol, 2012).

Very high potential use of hypoxia-related biomarkers as predictive factors of

response to radiotherapy

HYPOXIA

Do we have other tools to predict hypoxia and its related radiotherapy response?

1Danish Head and Neck Cancer Group; DSS* Disease Specific Survival; LRC** Loco-Regional Control

Functional imaging modalities such as:

Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI)

Apparent Diffusion Coefficient Magnetic Resonance Imaging (ADC-MRI)

Diffusion-Weighted Magnetic Resonance Imaging (DWI-MRI)

PET with following tracers:

18F-fluoromisonidazolo (FMISO)

18Fluoroazomycin arabinoside (FAZA)

HYPOXIA

…and so the BiGART (Biology-guided Adaptative Radiotherapy) was born

Grau C, et al. Acta Oncologica 2013; Hugo JWL, et al. Nature 2013; Chang JH, et al. Acta Oncologica 2013; Heijmen L, et al. CROH 2012

showed promising results in identifying hypoxia, proliferation,

cell density and the sequential radio-resistance/response thus

better guiding the radiotherapy treatment and decoding

the tumour phenotype by a radiomics approach

The Epidermal Growth Factor Receptor (EGFR) has been studied as:

EGFR protein expression*

EGFR protein activation (phospfhorylated EGFR, pEGFR)

EGFR gene copy number*

EGFR polymorphisms

EGFR mutation

EGFR

*Better studied

Study Population Treatment EGFR measure Predictive value

Dassonville

199394 H&N PF; surgery +/- RT Protein expression Yes

Hitt 2005 46 H&N Ind chemo PCF Protein expression No

Etienne 1999 82 H&N CT→RT; CTRT Protein expression Yes

Grandis 1998 91 H&NSurgery +/- RT and

CTProtein expression No

Psyrri 200595

oropharynx

RT or surgery +/-

RTCTProtein expression (AQUA) Yes

Pectasides

2011102 H&N RT +/- CT

AQUA

FISH

Yes

No

Wheeler 2012154 H&N

39 H&N

Surgery

RT + cetuximabProtein expression Yes

Chung 2006 82 H&N Surgery; RT/CT Gene amplification (FISH) Yes

EGFR seems to represent a powerful prognostic parameter especially when EGFR expression was measured in terms of producted protein by a “quantitative” method but a real

and certain prognostic role of EGFR in head and neck cancer has not been identified yet

PF = Cisplatin + 5-Fluoruracil; PCF = Paclitaxel + Cisplatin + 5-Fluorouracil; CT = chemotherapy; RT = radiotherapy;

RT/CT or CTRT = concomitant chemo-radiotherapy

EGFR: PROGNOSTIC ROLE?

EGFR: PREDICTIVE ROLE (1)?

Eriksen and Bentzen showed benefit in locoregional control rate (LRC) in patients with high EGFR expression treated with accelerated fractionation radiotherapy

(CHART). Further studies needed to validate this result


Chang 2008 50 glottisConventional or

hypofract RTProtein expression No

Ang 2002 268 H&N Protein expression No

Chung 2011 533 H&NAccelerated or

standard fract RTProtein expression No

Eriksen 2005 209 larynxPrimary RT, OTT:

9½, 6½ or 5½ wksProtein expression Yes

Bentzen 2005 304 H&NCHART vs conv

fract RTProtein expression Yes


Licitra 2011 312 H&NPlatinum based CT

+/- CetuxGene copy number (FISH) No

Licitra 2013 411 H&NPlatinum based CT

+/- CetuxProtein expression No

Hitt 2012 46 H&NPaclitaxel +

cetuximab

Protein expression or gene

copy nrNo

Tinhofer 2011 47 H&NDocetaxel +

cetuximab

Protein expression

EGFRvIII expressNo*

Burtness 2005 117 H&NCisplatin +/-

cetuximab

Cytoplasmatic expression

(IHC)No

Argiris 2010 39 H&NTPE→RT +

cddp/cetuximabGene copy number (FISH) No

EGFR: PREDICTIVE ROLE (2)?

No predictive role was identified for EGFR in head and neck cancer patientstreated with EGFR inhibitors

*High expression levels of EGFRvIII significantly correlated with lower PFS

TPE = Docetaxel + Cisplatin + Cetuximab; CDDP = Cisplatin

Not so common such as in other kind of tumours (e.g. NSCLC or glioblastoma

multiforme)

In head and neck cancer the percentage of EGFR mutations varies from 4 to 16%

The most frequent is EGFRvIII, which is a variant of EGFR with: truncated

extracellular domain constitutive activation of the intracellular tyrosine kinases

All EGFR mutations in head and neck cancer were not related to different treatment

outcome or prognostic significance

EGFR MUTATIONS IN HEAD AND

NECK CANCER

TP53 GENE MUTATION

AND SURVIVAL

Poeta ML, et al. N Engl J Med. 2007 Dec 20; 357(25): 2552–2561

Copyright © (2007) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society

TP53 GENE MUTATION

AND SURVIVAL

Poeta ML, et al. N Engl J Med. 2007 Dec 20; 357(25): 2552–2561

Not all the mutations are created equal…..

Copyright © (2007) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society

TP53 GENE MUTATION:

PREDICTIVE ROLE?

pCR Non-PCR

p53 mutations 27% 53%

p53 non functional mutations 14% 51%

p53 functional mutations 86% 49%

But not all mutations are created equal…..

A relationship between TP53 gene mutations and a lower response

rate to cisplatin-based neoadjuvant chemotherapy was found in head

and neck squamous cell cancer patients*

* Temam S, et al. JCO 2000; Cabelguenne A, et al. JCO 2000; Sullivan A, et al. Oncogene 2004

Further studies are needed to

validate any prognostic and

predictive role for TP53 in Head

and Neck Cancer

Molecular assessement of p53

has been hypothesised to help

histopathological staging of Head

and Neck Cancer but its role is

still to be confirmed

TP53

Brennan JA, et al. N Engl J Med 1995; 332:429-435. Copyright © (1995) Massachusetts Medical Society.

Reprinted with permission from Massachusetts Medical Society

*

*

* p53 negative or positive margins

BIOMARKERS: FUTURE

DIRECTIONS

Current prognostic biomarkers clearly do not serve as predictive biomarkers and,

at this time, cannot provide information regarding

how patients should be treated differently

This goal can only be achieved by a comprehensive understanding of

the biology, genetic and epigenetic alterations of HNC

To date, genomic data from two large genome-wide sequencing studies (Agrawal

2011, Stransky 2011) and a cancer-gene-targeted sequencing study of HNCs

(TCGA) are available

BIOMARKERS: STARTING FROM

THE GENETICS

Kang H, et al. Emerging biomarkers in head and neck cancer in the era of genomics. Nat Rev Clin Oncol 2015;12:11–26

Reprinted by permission from Macmillan Publishers Ltd: copyright (2014)

More frequent TSGs mutations than oncogene mutations

Of the 15 most-frequent mutations involved in HNCs, only 2 genes are known oncogenes

(1 out of these two oncogenes is potentially targetable)

TSGs are poor therapeutic targets because restoring loss-of-function in these genes is more difficult

than inhibiting increased activity resulting from gain-of-function in oncogenes

HPV positive HNCs patients have a lower average number of mutations compared to HPV negative

HNCs patients

GENE EXPRESSION PROFILES:

POTENTIAL PROGNOSTIC AND

PREDICTIVE ROLE 1st subgroup: Basal

High expression of TGF-alfa and other EGFR ligands

High activation of EGFR pathway genes

High expression of cadherin, laminin, collagen, bullous

pemphigoid antigen (basal-like subtype)

Worst clinical outcome

Potential benefit from EGFR-inhibitors

2nd subgroup: Mesenchymal

High expression of genes tipically produced by

fibroblasts/mesenchimal cells

Including tumours that may have undergone an epithelial

to mesenchymal transition

3rd subgroup: Atypical

High expression of Cytokeratin 15, Cytokeratin 4

Including normal tonsil epithelium samples

4th subgroup: Classical

Very similar gene-expression pattern to that induced by

exposure to cigarette smoke

Many genes of antioxidant –induced enzymes

Reprinted from Cancer Cell, Vol 5, Issue 5, Chung CH, et al. 489-500, Copyright (2004), with permission from Elsevier

COMPARABLE RESULTS OF GENE

EXPRESSION PROFILES:

Walter V, et al.

PLOS one 2013

De Cecco L, et al.

Oncotarget 2015

Chung CH, et al.

Cancer Cell 2004


POTENTIAL PROGNOSTIC ROLE

Kaplan-Maier (recurrence-free) survival analysis

of subgroup 1 vs. subgroup 2-4 (combined) from

Chung analysis

Kaplan-Maier (recurrence-free) survival analysis of

subgroup 1 vs. subgroup 2 vs. subgroup 3 + 4

(combined) from Chung analysis

Reprinted from Cancer Cell, Vol 5, Issue 5, Chung CH, et al. 489-500, Copyright (2004), with permission from Elsevier

C = Predicted cures

R = Predicted recurrences

Chung CH, et al. (Cancer Cell 2006) subsequently identified groups of patients at high or

low-risk for recurrence (out of mainly surgically treated patients with and without

postoperative radiotherapy or chemotherapy) by identification of a 42-gene signature


POTENTIAL PROGNOSTIC ROLE

Pramana J, et al. (Int Rad Oncol Biol

Phys 2007) tested this 42-gene

signature on 92 biopsies from

untreated head and neck cancer

patients, subsequently given cisplatin-

based chemoradiation for locally

advanced head and neck squamous

cell carcinoma. Authors identified that

this 42-gene high risk signature as

predicting factor of worse outcomes

(DFS* and LRC**) after chemo-

radiotherapy compared to low-risk

gene signature.

Reprinted from Int Rad Oncol Biol Phys 2007, 69 (5), 1544-52, Pramana J, et al. Copyright (2007), with permission from Elsevier

DFS* Disease Free Survival; LRC** Loco-Regional Control

GENE EXPRESSION PROFILES: POTENTIAL

PROGNOSTIC ROLE

De Cecco L, et al. Annals of Oncology 2014; 1-7,doi:10.1093/annonc/mdu173

By permission of Oxford University Press and ESMO

By a meta-analysis approach, starting from 3 publicly available HNCs microarray

datasets, a 172-gene signature (regardless of HPV status) was identified as able to

stratify HNC patients between high or low risk of relapse

Presented at: Hammerman P, ASCO 2015

IMMUNE CHEKPOINT-RELATED:

PD-L1 / PD1 PATHWAY

Basis for immune therapy - immune escape

Programmed cell death receptor 1 (PD-1)

is a negative co-stimulatory receptor

expressed primarily on activated T cells1,2

Tumour infiltrating lymphocytes (TILs)

induce cells in the tumour

microenvironment to express PD-L1 and

to bind PD-1 receptor to suppress

immune surveillance1,2

Clinical prognosis correlates with

presence of TILs and PD-L1 expression

in multiple cancers, including HNSCC3

1. Adapted from: Pardoll DM, Nat Rev Cancer 2012;12:252–64; Reprinted by permission from Macmillan Publishers Ltd, copyright (2012)

2. Saloura V, et al. J Clin Oncol 2014;32 (abstract); 6009

3. Lyford-Pike S, et al. Cancer Res 2013;73(6):1733-1741

IMMUNE CHEKPOINT-RELATED

PATHWAY: PD-L1 PD1

Herbst RS, et al. Nature, 515, 563–567 (27 November 2014) Reprinted by permission from Macmillan Publishers Ltd: copyright (2014)

Herbst RS, et al. Nature, 515, 563–567 (27 November 2014)

BIOMARKERS:

PD-1/PD-L1 EXPRESSION?

Reprinted by permission from Macmillan Publishers Ltd: copyright (2014)

*

* IHC (IC) score = Percentage of PD-L1-positive tumour-infiltrating and tumour cells detected by immunohistochemistry

The loss of chromosome region 9p21–22 is the most common of all genetic

changes in HNSCC at a frequency of 70% and occurs early in the progression of

head-and-neck tumours

Another example is the loss chromosome region 3p

Thirty percent of benign hyperplastic lesions, the earliest of precancerous lesions,

exhibited loss at either 9p21 or 3p

Patients with precancerous lesions showing these mutations have been

demonstrated at a significant higher risk of cancer development

BIOMARKERS OF

PRECANCERISATION

Thank you!

Documents

E-Learning Prognostic and Predictive Biomarkers in Head & Neck … · A prognostic biomarker indicates the likely course of the disease in untreated patients (or regardless of treatment)