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
Ex-Senior Resident, Dept. of Radiation Oncology, AIIMS, New Delhi
2. Overview of thepresentation
– 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
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
4. HN Ca: Disease Presentation
Early(I-II) 15-30 T1-2
LA(III-IV) 60-80 T3-4
Metastatic 2-15 N0-1 54
1. Choong N. CA 2008;58:32-53.
2. Mohanti et al. JLO 2007; 121:49-56
5. Head and Neck Ca: Failureand
• 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-
– Forastiere AA, Goepfert H, Maor M. NEJM.2003;349:2091-
• Detecting Recurrences:
– Clinical Examination
– CT Surveillance
– 18F FDG PET/CT
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
7. What`san ideal biomarker??
• Ability to diagnosecancersand pick up
recurrencesin asymptomatic cases
• Should beprognostic and predictive
• Serveasatherapeutic target
21. Subset analysis of patients enrolled in RTOG 0129 trial. (CFRT vs.
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
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
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) .
26. ONGOING TRIALS ON HPV + OPC:
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
•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
HPV + OPC
3 cycles of ICT with
Taxol + CDDP+ Erbitux
54Gy of CF
AF IMRT (69.6
27. • Head and Neck cancersdocumented to have
HPV-16 virusin their tumorsand suitablefor
Neoadjuvant CTRT f/b Therapeutic neck
35. EGFR: ResistancePathways
• Activation of ERBB2 signaling
• Mutant EGFR vIII
• ERK/AKT activation by IGFR-1
• Src/STAT mediated transactivation of EGFR
36. EGFR vIII
• EGFRvIII hasbeen detected in up to 40% of
• In vitro, cellsthat expressEGFRvIII havebeen
shown to belesssensitiveto thegrowth-
inhibiting effectsof cetuximab.
• EGFRvIII mutationsarealatestageevent
caused by therapid proliferation induced by
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
• 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
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
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
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
• 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.
47. Early Diagnosis
β- Tubulin Isoform
HPV –ve, High CIN
HPV –ve , Low CIN
BIOMARKERS IN HNCa
BIOMARKERS IN HNCa
RTto N0 Neck in
between HPV status
and EGFR targeting??
based on biomarkers
BIOMARKERS IN HNCa
Division of Hematology and Oncology, University of Pennsylvania, 3400 Civic Center Blvd, 2PCAM, Philadelphia, PA
DNA-based marker assays might detect gene mutations, deletions, amplifications, or methylation. RNA-based marker assays, which include a recently described class of molecules designated micro-RNAs (miRNA) might detect over- or underexpression of the message, splice differences in the message, or inhibitory miRNAs that prevent translation of other transcripts. Protein-based markers can include overexpression, underexpression, or qualitative abnormalities. One might detect cancer cells in tissues or fluid in which they do not belong, such as regional lymph nodes, circulation, or distant organs (like bone marrow). Detection of abnormal tissue processes induced by an existing cancer, such as neovascularization, can also serve as a marker. An assay for a marker might be for a single molecule, such as amplification of a specific gene or overexpression of a single protein, or it might include a multiparameter analysis, resulting in an index (analogous to using TNM [tumor, necrosis, metastasis] to create a tumor stage) or a profile or “signature,” most commonly developed within gene expression microarray technologies
TheCDKN2A gene locus found at chromosome 9p21 encodes two different transcripts, p16 and p14,which are responsible for cell cycle regulation and degradation of p53 respectively.
HPV is an ~7.9-kb, non-enveloped, double-stranded, circular DNA virus that has a specific tropism for squamous epithelium.
HPV-positive tumors tend to have a poorly differentiated and frequently basaloid histology that often lacks keratin.
patients with HPV-positive HNSCC are approximately 5 years younger than HPV-negative HNSCC patients, with equal distribution among the sexes. HPV-positive HNSCC is more likely than HPV-negative HNSCC to occur in the nonsmoker and nondrinker. Risk factors for HPV-related HNSCC include a high lifetime number of vaginal-sex partners (26 or more), a high lifetime number of oral-sex partners (6 or more),111 and seropositivity for HPV-16 viral capsid protein antibodies,82 which carries a 15-fold increased risk for HNSCC
The reason for the improved survival is unclear; however, improved radiation responsiveness, immune surveillance to viral antigens, and the absence of field cancerization in these patients who tend to be nonsmokers have been postulated as possibilities. In addition, E6-related degradation of p53 in HPV-positive cancers may not be functionally equivalent to HPV-negative p53 mutations, and therefore HPV-positive tumors may have an intact apoptotic response to radiation and chemotherapy
Figure 01:Range of EGFR Expression. KK Ang
Mod (mean absorbance),SI (Staining Index), QS(Quick score)