hpv-negative scc cancer: hpv-positive and the …...the changing landscape of oral cancer:...

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.


HPV-negative SCC

Anatomy

• Oral cavity

• Pharynx

– Nasopharynx– Oropharynx– Hypopharynx

• Larynx

• Esophagus

• Nasal cavity/paranasal sinuses

• Salivary glands

• Thyroid/parathyroid


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.


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


HPV-negative SCC

Smoking Prevalence

www.cdc.gov


HPV-negative SCC

http://www.cdc.gov/

Head and Neck Cancer Incidence Rates


HPV-negative SCC

Chaturvedi A K et al. JCO 2011

Oropharyngeal SCC Incidence


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


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)


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


HPV-negative SCC

HPV Induced Carcinogenesis


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


HPV-negative SCC

Gillison et al. JAMA. 2012

Prevalence of Oral HPV Infection


HPV-negative SCC

Gillison, JAMA. 2012.

Incidence and Clearance of Oral HPV

Kreimer et al. Lancet. 2013


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


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


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


HPV-negative SCC

HPV-Mediated (p16+) Oropharyngeal Clinical Staging


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


HPV-negative SCC

Work-up

• Biopsy-Pathology/cytopathology• CT- bony cortex• MRI- marrow space, soft tissue• PET/CT- for staging for advanced stage

disease


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


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


HPV-negative SCC

National Comprehensive Cancer Network. 2015.

Oral Cavity


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


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)


HPV-negative SCC

Oropharynx


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


HPV-negative SCC

Traditional approaches to the oropharyngeal cancers

Mandibulotomy Pharyngotomy

Jatin Shah, Head and Neck Surgical Oncology, 4th Edition 2010


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


HPV-negative SCC

National Comprehensive Cancer Network. 2015.

TORS


HPV-negative SCC

TORS Radical Tonsillectomy


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


HPV-negative SCC

Ang et al. NEJM. 2010; Fakhry et al. JNCI. 2008.

HPV and Survival


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


HPV-negative SCC

HPV and Overall Survival


HPV-negative SCC

O’Sullivan et al. Lancet Oncology. 2016

HPV and Smoking


HPV-negative SCC

3-year OS93.0% vs. 70.8% vs. 46.2%

Ang et al. NEJM. 2010

Treatment Failure


HPV-negative SCC

Progression of Disease: Locoregional and Distant


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%)


HPV-negative SCC

Fakhry et al. JCO 2014

Patterns of Disease Progression


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


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)


HPV-negative SCC

Genomic Carcinogenesis


HPV-negative SCC

Leemans et al. Nature Reviews Cancer. 2018.

Signaling Pathways


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.


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.


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


HPV-negative SCC

Personalized Medicine

• Personalized medicine = precision medicine

• Management is tailored to the individual patient based on …

– Molecular biology

• Liquid biopsy


HPV-negative SCC

IBM.

OPTIMA 2


HPV-negative SCC

Conclusion

•Prevention, vaccination and early detection are key to reducing morbidity and mortality


HPV-negative SCC

Thank [email protected] (cell)

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hpv-negative scc cancer: hpv-positive and the …...the changing landscape of oral cancer:...

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