The Changing Landscape of Oral Cancer: HPV-positive and HPV-negative SCCNishant Agrawal, MDChief of Otolaryngology-Head and Neck SurgeryDirector of Head and Neck Surgical OncologySection of Otolaryngology-Head and Neck SurgeryDepartment of Surgery
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Disclosure Information
• I have no relevant financial relationships to disclose.
• I will not discuss off label use or investigational use in my presentation.
Objectives
• Review the clinically relevant features of head and neck cancer.
– Demographics– Epidemiology– Survival
• Discuss the molecular classification of HPV-positive and HPV-negative SCC.
• Discuss management guidelines of oral cancer.
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Anatomy
• Oral cavity
• Pharynx
– Nasopharynx– Oropharynx– Hypopharynx
• Larynx
• Esophagus
• Nasal cavity/paranasal sinuses
• Salivary glands
• Thyroid/parathyroid
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
HNSCC
• > 600,000 cases of HNSCC
– 6th most common cancer worldwide
• 5 year survival of ~40-60%
• Cancer mortality rates continue to decline in the US
• Incidence of some HNSCC has increased
Siegel et al. CA: A Cancer Journal for Clinicians. 2012.
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Risk Factors• Environmental
– Smoking– Alcohol– Betel quid (betel leaf, areca
nut, slaked lime)• Virus
– HPV– EBV
• Immunosuppression
• Heredity/germline
• Bad luck
– Replicative random errors• Unknown
– Increasing incidence of oral/oral tongue SCC
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Smoking Prevalence
www.cdc.gov
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Head and Neck Cancer Incidence Rates
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Chaturvedi A K et al. JCO 2011
Oropharyngeal SCC Incidence
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Chaturvedi A K et al. JCO 2011
Incidence of OPC in the US: SEER
Patel et al. Cancer. 2016
Percent change
Overall 62.6
Sex
Male 81.8
Female -1.6
Race
White 87.7
Black -18.3
Other 5.9
Age
30-39 68.5
40-49 73.1
50-59 81.2
60+ 51.3
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Two Diseases
• HPV negative• HPV positive
– Patient characteristics• Male • White• Younger• Improved ECOG status• Non-smoker or ≤20 pack years
– Site characteristics• Oropharynx
• Palatine and lingual tonsils• Unknown primary site
– Tumor characteristics• Smaller primary tumor (earlier T stage)
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
HPV
• Small, circular DNA viruses
• Over 200 unique types
• High (type 16 and 18) and low risk types
• About 80% of population have HPV exposure
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
HPV Induced Carcinogenesis
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Leemans et al. Nature Reviews Cancer. 2018.
Prevalence of oral HPV
• 7% of the US population has active oral HPV infection
• 3.7% have high risk
• 1% has HPV 16
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Gillison et al. JAMA. 2012
Prevalence of Oral HPV Infection
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Gillison, JAMA. 2012.
Incidence and Clearance of Oral HPV
Kreimer et al. Lancet. 2013
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Any HPV High-risk HPV HPV16
Cumulativeincidence
Time to clearance
HPV 16 Exposure and Risk of OPSCC
site Odds ratio* 95% CI
Lip 0.5 0.1-2.1
Tongue 2.8 1.2-6.7
Oral Cavity 3.6 0.5-26.3
Oropharynx 14.4 3.6-58.1
Nasal Cavity/Sinuses 2.6 0.5-14.1
Larynx 2.4 1.0-5.6
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
HPV seropositivity preceded a cancer diagnosis by 9 years on average
Mork et al. NEJM. 2001
Natural History of Oral HPV Infection
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Benson et al. Exp Anticancer. 2014
Molecular Classification
• Histologic morphology
• P16 IHC– Surrogate
– Standardized
– Inexpensive
– Universal availability
• HPV DNA/RNA ISH– More variability
• HPV DNA/RNA PCR/RT-PCR
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
HPV-Mediated (p16+) Oropharyngeal Clinical Staging
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
O’Sullivan et al. Lancet Oncology. 2016
Physical Examination
• Physical-inspection and palpation– Texture and color of upper
aerodigestive tract-irregularity, nodularity, ulceration
– Loose teeth– Tongue mobility– Trismus– V3 (mental nerve) numbness– Examination of the neck-30%
accuracy• LNs-size, shape, number,
mobility, and consistency• Thyroid
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Work-up
• Biopsy-Pathology/cytopathology• CT- bony cortex• MRI- marrow space, soft tissue• PET/CT- for staging for advanced stage
disease
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Treatment
– Early stage (stage I and II)• Surgery• Radiotherapy• HPV ?
– Advance stage (stage III and IV)• Surgery + radiotherapy +/- chemotherapy• Radiotherapy + chemotherapy
– New therapy• EGFR inhibitor (cetuximab)• Immunotherapy
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Two Diseases
• Oral cavity cancer– Early Stage
• Primarily surgical treatment– Advanced Stage
• Surgery followed by adjuvant therapy• Multi-modality clinical trial
• Oropharynx cancer– Historically large surgical approaches with disfiguring
treatments– New roles for minimally invasive (e.g. TORS)– Chemoradiation
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
National Comprehensive Cancer Network. 2015.
Oral Cavity
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Oral Cancer Surgical Approaches
• Surgical Approaches
– Transoral– Mandibulotomy– Cheek flap with lip split– Visor flap– Lateral rhinotomy with
lip split– Lingual mandibular
release
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Shah et al. Oral Oncology. 2009.
Surgical Approach
• Tumor size
• Tumor site
• Proximity to mandible or maxilla
• Need for reconstructive surgery
• (Lots of overlap)
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Oropharynx
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Oropharynx
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Oropharynx
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Oropharynx cancer in the HPV era
• Smaller primary
• Larger nodal disease burden
• Adult neck mass is cancer until proven otherwise!
• Fine needle aspiration, not incisional biopsy should be the first line of investigation
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Traditional approaches to the oropharyngeal cancers
Mandibulotomy Pharyngotomy
Jatin Shah, Head and Neck Surgical Oncology, 4th Edition 2010
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
OPSCC and TORS• Historically large surgical approaches
with disfiguring treatments
• Surgical option must offer limited morbidity with excellent function (organ-sparing) and oncologic outcomes
• New roles for minimally invasive approaches (e.g. TORS)
– FDA approval for transoral surgery in 2009
– T1-T2, N0-N2 SCC of the tonsil and BOT
– Concurrent neck dissection is performed at the time of TORS
– Appropriate staging and determination of appropriate adjuvant therapy
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
National Comprehensive Cancer Network. 2015.
TORS
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
TORS
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
TORS Radical Tonsillectomy
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
TORS Radical Tonsillectomy
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
HNSCC• 5 year survival
– Stage I-II• 70-90%• HPV positive
– Stage III-IV (HPV negative)• 30-60%
• Metastasis to cervical lymph nodes has markedly negative impact on prognosis
• HPV association has markedly positive impact on prognosis
• Failure
– Loco-regional recurrence– Metastasis– Second primary malignancy
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Ang et al. NEJM. 2010; Fakhry et al. JNCI. 2008.
HPV and Survival
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
3- year OS82.4 vs. 57.1%
3- year PFS73.7 vs. 43.4%
Ang et al. NEJM. 2010
HPV and Overall Survival
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
HPV and Overall Survival
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
O’Sullivan et al. Lancet Oncology. 2016
HPV and Smoking
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
3-year OS93.0% vs. 70.8% vs. 46.2%
Ang et al. NEJM. 2010
Treatment Failure
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Progression of Disease: Locoregional and Distant
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
3 year: 17.3% v 32.5% P<0.001
3 year: 6.5% v 17.0% p=0.005
Ang et al. JCO 2014;32:2940-2950
Time to Disease Progression
• Median follow-up post progression: 4 years
• Median time to disease progression: p16-positive vs. p16-negative
• 8.2 vs. 7.3 months, p=0.67
• Majority of disease progressions occurred year 1 for p16-positive and p16-negative (65 vs. 63%)
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Fakhry et al. JCO 2014
Patterns of Disease Progression
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Fakhry et al. JCO 2014
De-intensification/de-escalation impetus
• Quality of life
– Chronic dysphagia• At 24 months after XRT
– 15% of patients had grade >= 2 swallowing dysfunction– 8% had progressive dysphagia
– Chronic xerostomia– Psychosocial impact
• Patients accept marginal lower survival versus severe treatment to avoid toxicity
• 81% of patients indicated they preferred reduced treatment
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Brotherston et all. Head Neck. 2013; Maxwell et al. Laryngoscope. 2014; Christianem et al. Radiother Oncol. 2015; Samuels et al. Oral Oncol. 2016; Curran et al. JCO. 2007; Gold. Oto Clinics NA. 2012;
De-intensification/de-escalation approaches• Reducing intensity/dose of a given modality without compromising efficacy
– Chemotherapy• Induction chemotherapy
– If favorable response, radiation dose de-escalation (Cmelak et al. JCO. 2014)• Omit chemotherapy
– Patients at low risk of distant metastatic disease (T1-3, N0-2a) may be treated with XRT alone (O’Sullivan et al. JCO. 2013)
• Targeted therapy– Cetuximab
» Ongoing RTOG 1016 trial to evaluate cetuximab + XRT versus cisplatin + XRT in p16+ OPSCC
– Immunotherapy– Radiation therapy-toxicity is dose dependent
• Dysphagia increases with every 10 Gy above 55 Gy delivered to the constrictors• Reduce overall dose of radiation to < 60 Gy
– Surgery• TORS
– Pathologic staging– Surgery followed by risk-adapted adjuvant treatment (ECOG 3311)
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Genomic Carcinogenesis
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Leemans et al. Nature Reviews Cancer. 2018.
Signaling Pathways
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
TCGA. Nature. 2015.
Therapeutic Implications• HPV negative tumors
– Majority harbored inactivating mutations in tumor suppressor genes (TP53, CDKN2A, NOTCH1, FAT1)
• TP53 mutations were found in > 80% of tumors• Targets of therapeutic intervention were identified in
the majority of HNSCC (TCGA)– Effectiveness of molecularly targeted therapies
» Drivers» Actionable» Resistance
Agrawal et al. Science. 2011; Stransky et al. Science. 2011; TCGA. Nature. 2015.
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Therapeutic Implications
• HPV positive tumors
– Lower mutation load– Activating mutations of PIK3CA– Amplification of cell cycle gene E2F1– Inactivation of TNF receptor-associated factor 3
(TRAF3)– TP53 mutations are rare – Inflammatory phenotype (prominent tumor
infiltration with CD8+ lymphocytes)Agrawal et al. Science. 2011; Stransky et al. Science. 2011; TCGA. Nature. 2015. Keck et al. CCR. 2015.
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Application of Genomic Profiling in HNSCC
Chung et al. Head and Neck. 2016.
Advanced recurrent or metastatic disease
refractory to standard of care therapies
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Personalized Medicine
• Personalized medicine = precision medicine
• Management is tailored to the individual patient based on …
– Molecular biology
• Liquid biopsy
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
IBM.
OPTIMA 2
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Conclusion
•Prevention, vaccination and early detection are key to reducing morbidity and mortality
The Changing Landscape of Oral Cancer: HPV-positive and
HPV-negative SCC
Thank [email protected] (cell)
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