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Dr Ajeet Kumar Gandhi
MD (AIIMS, New Delhi);DNB;MNAMS; UICCF (MSKCC,USA)
Assistant Professor, Department of Radiation Onco...
Overview of thepresentation
• Introduction
– Head and Neck cancers: Theneed for Research
– Biomarkersand Molecular Classif...
Around 6.4 lakh cases of head and neck cancers diagnosed world wide per year
Around 1.5 lakh cases diagnosed in India per ...
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...
Head and Neck Ca: Failureand
Detection
• Estimated Loco-regional failure rates between 20-50% after
multimodality therapie...
What areBiomarkers??
• A biomarker isamolecular or tissue-based processthat
providesfuturebehaviour of acancer but require...
What`san ideal biomarker??
• Ability to diagnosecancersand pick up
recurrencesin asymptomatic cases
• Should beprognostic ...
Biology of HNCa: Multistep
carcinogenesisand Molecular
Heterogeneity
05/01/17 8
Heterogeneity of HNCa
• morethan 95% of head and neck cancersare
squamouscell carcinomassuggeststhat it isa
relatively hom...
Loss of chromosomal region
9p21 is found in 70%–80% of cases, thus representing
the most common genetic alteration seen in...
Genetic Alterations:Head and Neck
cancers
05/01/17 11
05/01/17 12
TowardsPersonalization
05/01/17 13
Biomarkersfor Diagnosis
• Diagnosisof NPCa:
– VCA IgA
– Gp78 + VCA Ig + EBNA Ig
– EBER (EBV encodeRNA)
05/01/17 14
Predictive& Prognostic Factors
• PredictiveFactors:
– ERCC1:Cisplatin sensitivity
– β Tubulin Isoform III: Taxanesensitivi...
05/01/17 16
05/01/17 17
05/01/17 18
Biomarkers:Prognostication
• EBV titre<1,500 copies/mL had increased OS
and RFS. Persistently elevated EBV titre1
week aft...
HPV
05/01/17 20
 Subset analysis of patients enrolled in RTOG 0129 trial. (CFRT vs.
AcFRT).
 Total OPC were 60.1% of all patients (n=433...
05/01/17 22
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...
Oropharynx Tumour, HPV Status And 2 year survival:
ECOG 2399 STUDY
05/01/17 24
Summary of HPV Trials
05/01/17 25
ONGOING TRIALS ON HPV + OPC:
De-intensification
ECOG 1308 ( Phase II RCT)
RTOG 1016 – PHASE III RCT
• Locally advanced OPC...
• Head and Neck cancersdocumented to have
HPV-16 virusin their tumorsand suitablefor
Neoadjuvant CTRT f/b Therapeutic neck...
EGFR Pathway
05/01/17 28
05/01/17 29
Cetuximab in Recurrent head and
neck cancers
05/01/17 30
EGFR: Why wehavefailed to
deliver??
• EGFR: Do weneed assaysand quantification
of marker
• EGFR : Resistancepathwaysand do...
EGFR: Prognostic marker and
predictor for loco-regional relapse
05/01/17 32
05/01/17 33
05/01/17 34
EGFR: ResistancePathways
• Activation of ERBB2 signaling
• Mutant EGFR vIII
• AuroraKinaseActivation
• ERK/AKT activation ...
EGFR vIII
• EGFRvIII hasbeen detected in up to 40% of
SCCHN cases.
• In vitro, cellsthat expressEGFRvIII havebeen
shown to...
An open-label, randomized, study of h-R3mAb
(nimotuzumab) in patients with advanced (stage IIIor
IVa) squamous cell carcin...
STAT3 Pathway
05/01/17 38
Radioresistance
• PI3/AKT Pathway up regulated in irradiated
tumors:
– Intrinsic radio-resistance
– Tumor cell proliferati...
Biomarkersand HNCaSurgery
05/01/17 40
05/01/17 41
05/01/17 42
Avenuesfor Newer Research
• Stem cell markers:
– In early stagelaryngeal cancer treated with
radiotherapy alone, expressio...
Biomarkers: Therapeutic Targets
• EGFR Pathway:
– Cetuximab
– Panitumumab,Zalutumumab,Nimotuzumab
• Small MoleculeInhibito...
05/01/17 45
Key Conclusions: I
• ERCC1 expression: Expression may berelevant for
responseto platinum therapy, needsfurther validation....
Early Diagnosis
of Cancer:
p16/p53/LOH 18q
VCA IgA,EBER
Predicting Response
to concurrent
Therapy:
ERCC1/RRM1
β- Tubuli...
Association
between HPV status
and EGFR targeting??
 Adequate
radiation dose
fractionation
and Dose??
Patient selection
...
Thank yo uThank yo u
05/01/17 49
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Biomarkers in head and neck cancers final ajeet

Exploring the role of biomarkers in head and neck cancers

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Biomarkers in head and neck cancers final ajeet

  1. 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. 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 05/01/17 2
  3. 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 05/01/17 3
  4. 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; 121:49-56 405/01/17
  5. 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 505/01/17
  6. 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 05/01/17 6
  7. 7. What`san ideal biomarker?? • Ability to diagnosecancersand pick up recurrencesin asymptomatic cases • Should beprognostic and predictive • Serveasatherapeutic target 05/01/17 7
  8. 8. Biology of HNCa: Multistep carcinogenesisand Molecular Heterogeneity 05/01/17 8
  9. 9. Heterogeneity of HNCa • morethan 95% of head and neck cancersare squamouscell carcinomassuggeststhat it isa relatively homogeneousdisease 05/01/17 9
  10. 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 05/01/17 10
  11. 11. Genetic Alterations:Head and Neck cancers 05/01/17 11
  12. 12. 05/01/17 12
  13. 13. TowardsPersonalization 05/01/17 13
  14. 14. Biomarkersfor Diagnosis • Diagnosisof NPCa: – VCA IgA – Gp78 + VCA Ig + EBNA Ig – EBER (EBV encodeRNA) 05/01/17 14
  15. 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(??) 05/01/17 15
  16. 16. 05/01/17 16
  17. 17. 05/01/17 17
  18. 18. 05/01/17 18
  19. 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. 05/01/17 19
  20. 20. HPV 05/01/17 20
  21. 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. 05/01/17 21
  22. 22. 05/01/17 22
  23. 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) . 05/01/17 23
  24. 24. Oropharynx Tumour, HPV Status And 2 year survival: ECOG 2399 STUDY 05/01/17 24
  25. 25. Summary of HPV Trials 05/01/17 25
  26. 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) 05/01/17 26
  27. 27. • Head and Neck cancersdocumented to have HPV-16 virusin their tumorsand suitablefor Neoadjuvant CTRT f/b Therapeutic neck disection 05/01/17 27
  28. 28. EGFR Pathway 05/01/17 28
  29. 29. 05/01/17 29
  30. 30. Cetuximab in Recurrent head and neck cancers 05/01/17 30
  31. 31. EGFR: Why wehavefailed to deliver?? • EGFR: Do weneed assaysand quantification of marker • EGFR : Resistancepathwaysand downstream signalling 05/01/17 31
  32. 32. EGFR: Prognostic marker and predictor for loco-regional relapse 05/01/17 32
  33. 33. 05/01/17 33
  34. 34. 05/01/17 34
  35. 35. EGFR: ResistancePathways • Activation of ERBB2 signaling • Mutant EGFR vIII • AuroraKinaseActivation • ERK/AKT activation by IGFR-1 • Src/STAT mediated transactivation of EGFR 05/01/17 35
  36. 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. 05/01/17 36
  37. 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 05/01/17 37
  38. 38. STAT3 Pathway 05/01/17 38
  39. 39. Radioresistance • PI3/AKT Pathway up regulated in irradiated tumors: – Intrinsic radio-resistance – Tumor cell proliferation – Hypoxia:HIF-1 α mediated 05/01/17 39
  40. 40. Biomarkersand HNCaSurgery 05/01/17 40
  41. 41. 05/01/17 41
  42. 42. 05/01/17 42
  43. 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 05/01/17 43
  44. 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 05/01/17 44
  45. 45. 05/01/17 45
  46. 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. 05/01/17 46
  47. 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 05/01/17 47
  48. 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??? 05/01/17 48
  49. 49. Thank yo uThank yo u 05/01/17 49

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