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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 youna@uchicago.edu410-274-0325 (cell)

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