1. Dr Ajeet Kumar Gandhi
MD (AIIMS, New Delhi);DNB;MNAMS; UICCF (MSKCC,USA)
Assistant Professor, Department of Radiation Oncology
Dr Ram Manohar Lohia Institute of Medical Sciences, Lucknow
(http://www.drrmlims.ac.in/radiationoncology1.php#)
Ex-Senior Resident, Dept. of Radiation Oncology, AIIMS, New Delhi
05/01/17 1

2. Overview of thepresentation
• Introduction
– Head and Neck cancers: Theneed for Research
– Biomarkersand Molecular Classification
• Roleof Biomarkersin
– Diagnosisand screening
– Prognosisand prediction
– Therapeutic targetsand recent concepts
– Detection of recurrencesand follow up
• Conclusion
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3. Around 6.4 lakh cases of head and neck cancers diagnosed world wide per year
Around 1.5 lakh cases diagnosed in India per year accounting for ~20 % of all cancer cases
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4. HN Ca: Disease Presentation
Stage1
Rate(%) TNM2
Rate(%)
At Presentation
Early(I-II) 15-30 T1-2
20
LA(III-IV) 60-80 T3-4
80
Metastatic 2-15 N0-1 54
1. Choong N. CA 2008;58:32-53.
2. Mohanti et al. JLO 2007; 121:49-56
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5. Head and Neck Ca: Failureand
Detection
• Estimated Loco-regional failure rates between 20-50% after
multimodality therapies and ~30% for surgery f/b PORT
– Calais G, Bardet E, Sire C. IJROBP 2004;58:161-166
– Lefebvre JL, Chevalier D, Luboinski B. JNCI.1996;88:890-
899
– Forastiere AA, Goepfert H, Maor M. NEJM.2003;349:2091-
2098
• Detecting Recurrences:
– Clinical Examination
– CT Surveillance
– 18F FDG PET/CT
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6. What areBiomarkers??
• A biomarker isamolecular or tissue-based processthat
providesfuturebehaviour of acancer but requiresa
special assay that isbeyond routineclinical,
radiographic, or pathologic examination
• Tumor markerscan bemeasured at multiplelevels:
DNA, RNA, protein, cell, and tissue.
– DNA-based marker assays: FISH,PCR
– RNA-based marker assays: RT-PCR
– Protein-based markers: IHC
– Detection of abnormal tissueprocessesinduced by an
existing cancer, such asneovascularization
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7. What`san ideal biomarker??
• Ability to diagnosecancersand pick up
recurrencesin asymptomatic cases
• Should beprognostic and predictive
• Serveasatherapeutic target
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8. Biology of HNCa: Multistep
carcinogenesisand Molecular
Heterogeneity
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9. Heterogeneity of HNCa
• morethan 95% of head and neck cancersare
squamouscell carcinomassuggeststhat it isa
relatively homogeneousdisease
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10. Loss of chromosomal region
9p21 is found in 70%–80% of cases, thus representing
the most common genetic alteration seen in
squamous dysplasia and HNSCC
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11. Genetic Alterations:Head and Neck
cancers
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13. TowardsPersonalization
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14. Biomarkersfor Diagnosis
• Diagnosisof NPCa:
– VCA IgA
– Gp78 + VCA Ig + EBNA Ig
– EBER (EBV encodeRNA)
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15. Predictive& Prognostic Factors
• PredictiveFactors:
– ERCC1:Cisplatin sensitivity
– β Tubulin Isoform III: Taxanesensitivity
– HPV: Responseto CT and CTRT
– EGFR(?): Cetuximab sensitivity and responseto therapy
– (?)BCL-Xl: Larynx preservation and completeresponse
– (?)TIMP3 Methylation,RASSF1A/2A,CDH1 Methylation:
Predicting responseto radiation
• Prognostic Facors:
– EGFR
– HPV
– TGF-α , Bcl-2, Cyclin D1, CDH 1 Methylation(??)
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19. Biomarkers:Prognostication
• EBV titre<1,500 copies/mL had increased OS
and RFS. Persistently elevated EBV titre1
week after completion of sequential chemoRT
had worseOS, RFS*
*Lin JC. N Engl JMed 2004;350(24):2461-
2470.
**Leung SF.JClin Oncol 2008;24:5414-
5418.
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20. HPV
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21.  Subset analysis of patients enrolled in RTOG 0129 trial. (CFRT vs.
AcFRT).
 Total OPC were 60.1% of all patients (n=433).
 HPV status evaluated in 74% of all ca OPx patients (n=323).
 HPV DNA was detected in 63.8% of patients’ tumors (206 of the 323)
by means of FISH, and 96.1% of the samples (198 of 206) were positive
for HPV-16.
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22. 05/01/17 22

23. ECOG 2399: HPV RESULTS
HPV + HPV -
OPC 38 (60%) 24
Lx 0 34
Total 38 (40%) 58 (60%)
 HPV + patients had higher PS (ECOG “0” in 66% of HPV +ve vs. 33% in
HPV –ve.
 Patients with HPV-positive tumors were more likely to report less than 20
pack-years of cigarette use (37% vs 0%, respectively, P < .001).
 HPV +ve patients were having more lingual or palatine tonsil primary
(84% vs 63%, respectively, P =0 .07) .
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24. Oropharynx Tumour, HPV Status And 2 year survival:
ECOG 2399 STUDY
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25. Summary of HPV Trials
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26. ONGOING TRIALS ON HPV + OPC:
De-intensification
ECOG 1308 ( Phase II RCT)
RTOG 1016 – PHASE III RCT
• Locally advanced OPC (n=700)
•Randomization is stratified by low
and high T stage, low and high N
stage, and smoking history (</> 10
pack years)
•Both arms of this trial will use
accelerated fractionation IMRT (70
Gy in 6 weeks).
•The control arm will receive two
cycles of Cisplatin, and the
experimental arm will receive weekly
Cetuximab.
Stage III-IVB
HPV + OPC
(n=83)
3 cycles of ICT with
Taxol + CDDP+ Erbitux
CR+
54Gy of CF
IMRT+Erbitux
CR-
AF IMRT (69.6
Gy/33 Fr)
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27. • Head and Neck cancersdocumented to have
HPV-16 virusin their tumorsand suitablefor
Neoadjuvant CTRT f/b Therapeutic neck
disection
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28. EGFR Pathway
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29. 05/01/17 29

30. Cetuximab in Recurrent head and
neck cancers
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31. EGFR: Why wehavefailed to
deliver??
• EGFR: Do weneed assaysand quantification
of marker
• EGFR : Resistancepathwaysand downstream
signalling
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32. EGFR: Prognostic marker and
predictor for loco-regional relapse
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34. 05/01/17 34

35. EGFR: ResistancePathways
• Activation of ERBB2 signaling
• Mutant EGFR vIII
• AuroraKinaseActivation
• ERK/AKT activation by IGFR-1
• Src/STAT mediated transactivation of EGFR
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36. EGFR vIII
• EGFRvIII hasbeen detected in up to 40% of
SCCHN cases.
• In vitro, cellsthat expressEGFRvIII havebeen
shown to belesssensitiveto thegrowth-
inhibiting effectsof cetuximab.
• EGFRvIII mutationsarealatestageevent
caused by therapid proliferation induced by
wild-typeEGFR overexpression.
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37. An open-label, randomized, study of h-R3mAb
(nimotuzumab) in patients with advanced (stage IIIor
IVa) squamous cell carcinoma of head and neck (SCCHN):
Four-yearsurvival results from a phase IIb study. JClinOncol
28:15s,2010(suppl; abstr5530)
• Presented in ASCO 2010
• 133 patientsof stageIII-IVaHNSCC
• Dose: RT-60-66 Gy/2 Gy/#/5# per week
Cisplatin-50mg/week x 6
Nimotuzumumab-200mg iv/hr weekly x 6
CTRT+nim CTRT RT+nim RT alone
Locoregional
response
rate(%)
100 70 76 37
OS rate (%) 47 21 (p – 0.01) 34 13 (p – NS)
Median OS (mo) NR 21.9 14.3 12.7
FU period - 4
years
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38. STAT3 Pathway
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39. Radioresistance
• PI3/AKT Pathway up regulated in irradiated
tumors:
– Intrinsic radio-resistance
– Tumor cell proliferation
– Hypoxia:HIF-1 α mediated
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40. Biomarkersand HNCaSurgery
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42. 05/01/17 42

43. Avenuesfor Newer Research
• Stem cell markers:
– In early stagelaryngeal cancer treated with
radiotherapy alone, expression of theputativestem
cell marker CD44 wasshown to predict local control
– 2 stem cell markersGRP78 (heat shock 70kDaprotein
5) and NANOG correlated with aworseprognosisin
HNSCC treated with surgery with or without
radiotherapy or chemotherapy
• EMT (Epithelial to Mesenchymal Transition)
• Epigenetic Modifications
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44. Biomarkers: Therapeutic Targets
• EGFR Pathway:
– Cetuximab
– Panitumumab,Zalutumumab,Nimotuzumab
• Small MoleculeInhibitor of TK:
– Gefitinib,Erlotinib
– Lapatinib, Afatinib(IrreversibleIsof EGFR and HER2),
Dacomitinib (IrreversibleIsof HER1-4)
• IGF Pathway : Figitumumab
• VEGF Pathway: Bevacizumab, Cediranib, Sorafenib,
Sunitinib, Pazopinib
• Non-Receptor Targets: PI3 Is/src kinaseIs,Dasatinib
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46. Key Conclusions: I
• ERCC1 expression: Expression may berelevant for
responseto platinum therapy, needsfurther validation.
• β-Tubulin Expression :of certain isotypesmay influence
responseto taxanes, needsfurther validation.
• HPV Strong prognostic factor, warrantsdedicated trial
designs
• EGFRPathway:
• EGFR Expression isuniversal in SCCHN ; over expression
isanegativeprognostic factor after RT.
• Quantification of EGFR expression needsfurther study.
• EGFRvIII May affect sensitivity to cetuximab, not yet
validated in theclinic.
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47. Early Diagnosis
of Cancer:
p16/p53/LOH 18q
VCA IgA,EBER
Predicting Response
to concurrent
Therapy:
ERCC1/RRM1
β- Tubulin Isoform
III
HPV
EGFR
Therapeutic Targets
and Overcoming
Resistance:
EGFR/HER2/VEGF
EGFRvIII/Aurora
kinase
Tailored Treatment
HPV+ve Tumors
HPV –ve, High CIN
HPV –ve , Low CIN
EGFR Pathway
Signature type
EXPLORING
BIOMARKERS IN HNCa
EXPLORING
BIOMARKERS IN HNCa
Better Therapeutic
Ratio
Tailored Treatment:
RTin Molecular+ve
margins
RTto N0 Neck in
STAT3 Mut
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48. Association
between HPV status
and EGFR targeting??
 Adequate
radiation dose
fractionation
and Dose??
Patient selection
based on biomarkers
for therapy???
 Combination of
chemoRT with
EGFR targeting???
EXPLORING
BIOMARKERS IN HNCa
Unanswered
Questions???
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49. Thank yo uThank yo u
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