1. HPV-Related Head and Neck Cancer
Guilherme Rabinowits M.D.
Center for Head and Neck Oncology
Instructor in Medicine
Harvard Medical School
Boston, MA

2. Disclosures Scientific Advisory Board for Onyx Pharmaceuticals Inc.
Clinical Trial Support to Institution from Exelixis and Millenium

3. Introduction HNC - 6th most common cancer worldwide
Historically tobacco and ETOH-related cancer
Strong evidence linking HPV infection to HNC
Increasing incidence of oropharynx cancers, while decrease incidence of other HNCs
Proportion of HPV+ disease is increasing: epidemic North European and North American patients
Preferentially identified in oropharynx cancer - tonsil and base of tongue
HPV 16 is the predominant subtype (>90%)
Ang NEJM 2010
Abogunrin BMC Cancer 2014

4. Patient and Tumor Characteristics
Younger patient population
Lower smoking rates
Men > women
Multiple sexual partners
Oral sex practice
Oropharynx most common location
Small primary tumors and advanced nodal disease
Cystic nodes
Poorly differentiated, basaloid tumors
Most pts with HPV+OPC are still men in their 50’s who have a smoking hx. True non-smokers constitutes only a minority
D’Souza NEJM 2007
Gillison JNCI 2008
Chatuverdi JCO 2011

5. Molecular and Biological Events in HNC5
HNC Can Now Be Divided Into 2 Large and Distinct Subtypes
HPV-Related Cancers
Environment-Related Cancers
Caused by high-risk HPV
HPV 16
Driven by viral oncogenes
Restricted to oropharynx
Distinct molecular markers
“Good” prognosis
Young, good general health
Caused by environmental mutagens
Smoking, alcohol
Throughout oral mucosa
Distinct molecular markers
“Poor” prognosis, comorbidity
Second primary cancers

6. Genomic Landscape Hayes et al ASCO 2013
PIK3CA activation promotes cell cycle activation, metabolism and trasncription factors that regulates diverse genes that promote the malignant phenotype
Given that both wild-type (vs mutant) p53 and lower EGFR expression are correlated with treatment responsiveness and survival, these biologic differences may in part explain the difference in outcomes based upon HPV status. Additionally, HPV-associated tumors may be less hypoxic, which could increase responsiveness to radiotherapy.
Hayes et al ASCO 2013

7. Proportion of Oropharynx Cancer, USA 1973-2005
New data from 2005 – 2011 revealed continuing alarming increases in age-specific incidence rates by birth cohort among all men born after 1940, age years
OPC is one of the only 5 cancer types that increased in incidence from 1975 – 2009 (CDC)
Jemal JNCI 2013
32%
18%
Chaturvedi and Gillison

8. Tumor HPV Prevalence
D’Souza Prev. Med 2011

9. Latency Period
Gillison JCO 2015

10. Screening Screening at this time for HPV+ OPC is infeasible
Inability to detect precursor lesions and subclinical or early-stage cancers
Absence of an established intervention to reduce cancer incidence and mortality

11. HPV Diagnostic Testing
p16 immunohistochemistry (very sensitive)
In situ hybridization for high risk HPV (very specific)
PCR (both sensitive and specific)
P16 IHC – procedural simplicity, ease of interpretation and excellent sensitivity
P16 IHC x HPV ISH ~25%
HPV-associated cases are determined based upon strong nuclear and cytoplasmic staining of at least 70% 11

12. HPV Oncoproteins Mohanti doi:10.4172/scientificreports.452
Integration of high-risk HPV DNA, into the human cellular genome is an important step in malignant transformation. The E6 oncoprotein disrupts the p53 pathway and causes subsequent degradation of the p53 protein, which results in loss of control at the G1/S and G2/M checkpoints making the cell susceptible to defective repair capacity as well as uncontrolled growth. The E7 oncoprotein is involved in the inactivation retinoblastoma tumor suppressor gene product pRb. Regulatory function of the Rb tumor suppressor protein appears to largely depend on the ability of Rb to bind to and inhibit the family of E2F transcription factors that encode proteins necessary for DNA synthesis, replication and maintenance of cell cycle regulation. The bound Rb-E2F protein serves as inhibitor of transcription for several genes regulating cell proliferation including p16 gene, phosphorylation of Rb leads to the release of the transcription factor E2F. The CyclinD-cdk4/6 complexes (CDKs), when not under the inhibition by p16 phosphorylate Rb leading to the release of the transcription factor E2F and initiating cell cycle progression. P16 regulates the activity of these CyclinD-cdk4/6 complexes. The E7 protein forms complexes with hypophosphorylated forms of the retinoblastoma tumor suppressor protein (pRb) resulting in release of E2F, thereby releasing p16 gene from its transcriptional inhibition and inducing transcription of various genes which lead to cell proliferation. Consequently HPV-positive tumors are characterized by high expression levels of p16 
Mohanti doi: /scientificreports.452

13. HPV Status as a Prognostic Factor
Modality
Time
HPV+
HPV- p
Radiation (DAHANCA)1
5 yrs
62%
26%
0.0003
ChemoRT (TROG)2
2 yrs
91%
74%
0.004
ChemoRT (RTOG 0129)3
3 yrs
82%
57%
0.001
Sequential (ECOG)4
95%
0.005
Sequential (TAX324)5
35%
0.0001
1Lassen, JCO, 2009; 2Rischin, JCO, 2010; 3Ang NEJM, 2010; 4Fakhry, JNCI, 2008; 5Posner Ann Onc, 2011

14. Treatment Toxicity
Acute: mucositis, dermatitis, dysphagia, odynophagia
Chronic: xerostomia, dysgeusia
Can therapy for all HPV+ OPC be deintensified to decrease risk of acute and long-term toxicities?
Are there other prognostic factors within OPC other than HPV status?

15. Stage III/IV (T2, N2-3, M0 or T3-4, any N, M0) SCCHN
RTOG 0129 Phase III Trial: Concomitant CRT With Standard vs. Accelerated Fractionation RT
CRT
Stage III/IV (T2, N2-3, M0 or T3-4, any N, M0) SCCHN
Oral cavity, oropharynx, hypopharynx, and larynx
No previous treatment
N=743
Cisplatin
(IV on d1, d22, d43)
Standard fractionation RT
(5 d/wk for 7 wks) R A N D O M I Z E
Cisplatin
(IV on d1 and d22)
Accelerated fractionation RT
(5 d/wk for 3.5 wks; then bid, 5 d/wk for 2.5 wks)
3-year OS, PFS or pattern of relapse were similar between groups
Ang NEJM 2010 15

16. RTOG 0129: HPV Analysis 433 (60%) of 721 had OP primary
323 (75%) of 433 had HPV testing
206 (64%) of 323 were HPV+
P16-positive
P16-negative
HPV-positive
192 (93%)
7 (3%)
HPV-negative
22 (19%)
94 (80%)
Kappa = 0.80: 95%CI
Ang NEJM 2010

17. RTOG 0129: OS and PFS by HPV Status
100 75 50 25 OS
100 75 50 25
PFS
OS (%)
HPV negative
HPV positive
HPV negative
HPV positive
HR=0.38 (95% CI: ); P<0.001
HR=0.40 (95% CI: ; P<0.001
3-Yr Outcomes
HPV Positive (%)
HPV Negative (%)
P Value OS
82.4
57.1
<0.001
PFS
73.7
43.4
Locoregional failure
13.6
35.1
Distant metastases
8.7
14.6
0.23
Ang NEJM 2010 17

18. RTOG 0129 RPA: HPV, Smoking Status, Staging
RPA: Statistical Method for Multivariable Analysis; Creates a Classification of a Population Based on Independent Variables
Ang NEJM 2010

19. Risk Groups Risk Characteristics 3-year OS Low HPV+, Non-Smoker
HPV+, Smoker N0-2a
93%
(95% CI, )
Intermediate
HPV+, Smoker, N2b-3
HPV-, Non-Smoker T2-3
71%
(95% CI, )
High
HPV-, Non-Smoker, T4
HPV-, Smoker
46%
(95% CI, )
Ang NEJM 2010

20. LC RC DC Retrospective analysis
OPC treated with RT or CRT
Risk of distant metastasis HPV+ OPC
Similar risk of distant metastasis despite differences in loco-regional control LC RC DC
HPV+
94%
95%
90%
HPV-
80%
82%
86%
P<0.01
P=0.53
Median f/u 3.9 years
O’Sullivan JCO 2013

21. PMH RPA HPV Positive Low Risk Modified
Multivariate analysis identified that HPV negativity (hazard ratio [HR], 2.9; 95% CI, 2.0 to 5.0), N2b-N3 (HR, 2.9; 95% CI, 1.8 to 4.9), T4 (HR, 1.8; 95% CI, 1.2 to 2.9), and RT alone (HR, 1.8; 95% CI, 1.1 to 2.5) predicted a lower recurrence-free survival.
More than 10 pack-year smokers had a lower 3-year OS compared with their ≤ 10 pack-year counterparts (77% [95% CI, 70% to 82%] v 89% [95% CI, 84% to 93%], respectively; P < .001) but similar RFS (86% [95% CI, 79% to 90%] v 83% [95% CI, 77% to 88%], respectively;P = .43). The late toxicity rate was marginally higher in more than 10 pack-year smokers (13% v 21% for ≤ 10 pack-year smokers; P = .06). A higher proportion of more than 10 pack-year smokers developed a second primary cancer (11% v 4% for ≤ 10 pack-year smokers; P = .009; Table 1).
HPV Positive Low Risk Modified
*N2c removed from final grouping
-Difference for RT vs CRT
*Also remove N2b heavy smokers
O’Sullivan JCO 2013

22. PMH Results HPV+ group recommended for deintensification:
Low risk: T1-T3, N0-N2c (DC 93%; LRC 95%)
High risk: T4, N3 (DC 78%; LRC 82%)
HPV-
Low risk: T1-T2, N0-N2c (DC 93%; LRC 76%)
High risk: T3-T4, N3 (DC 72%; LRC 62%)
The DC rates for HPV-positive, low-risk N0-2a or less than 10 pack-year N2b patients were similar for RT alone and CRT, but the rate was lower in the N2c subset managed by RT alone (73% v 92% for CRT; P = .02).
HPV+ group recommended for deintensification:
T1-T3, N0-N2a
T1-T3, N2b <10 Pack-Years
O’Sullivan JCO 2013

23. What about Clinical Trials and Future Directions?

24. Treatment Deintensification Strategies
Reduced radiation dose
Reduced concurrent chemotherapy dose
Substitute biologic agent for chemotherapy
Use induction chemotherapy to select responders and then reduce radiation dose 24 24

25. Cetuximab loading dose = 400mg/m2 on Day1 of Cycle1 with Induction
E1308: Phase II HPV-specific Trial Chemotherapy to Select Patients for Lower Dose Radiation
INDUCTION
(3 cycles)
Weekly Paclitaxel +
Weekly Cetuximab
Q3 wks Cisplatin
ELIGIBILITY
Stage III, IVA
Resectable
HPV or P16+ Oropharynx
CONCURRENT
IMRT 54Gy/27 fxs
Cetuximab 250mg/m2 qwk CR
CONCURRENT
IMRT 69.3Gy/33fxs
Cetuximab 250mg/m2 qwk
<CR
N=80
Cetuximab loading dose = 400mg/m2 on Day1 of Cycle1 with Induction

26. E1308: Results Endpoint: 2-year PFS and OS Cohort (n)
2-year PFS (90% CI)
2-year OS (90% CI)
All low dose pts (62)
0.8 (0.7, 0.88)
0.93 (0.85, 0.97)
T4a (7)
0.54 (0.19, 0.79)
0.86 (0.45, 0.97)
Non-T4a (55)
0.84 (0.73, 0.91)
0.94 (0.86, 0.98)
N2c (19)
0.77 (0.56, 0.89)
0.95 (0.76, 0.99)
Non-N2c (43)
0.82 (0.69, 0.9)
0.93 (0.82, 0.97)
Smoker > 10pk-yrs (22)
0.57 (0.35, 0.73)
0.86 (0.67, 0.94)
Smoker < 10 pk-yrs (40)
0.92 (0.81, 0.97)
0.97 (0.87, 0.995)
Smoker < 10pk-yrs, <T4, <N2c (27)
0.96 (0.82, 0.99)
All high dose pts (15; 3 didn’t get RT)
0.65 (0.41, 0.82)
0.87 (0.63, 0.96)
23% dose reduction in RT allowed for a significant reduction in toxicity while maintaining high PFS and OS
Cmelak ASCO 2014, adapted

27. RTOG 1016: A Randomized Phase III Trial of RT with Cisplatin or Cetuximab in P16+ OPC27
RANDOMIZE
Cisplatin 100 mg/m2/q21d
ELIGIBILITY
Stage
III, IVA/B
Resectable
P16+
Oropharynx
Cancer
IMRT
70Gy
Cetuximab 400/250 mg/m2 weekly
IMRT 70Gy
Stratify: HPV, smoking, stage
Cetuximab loading dose = 400 mg/m2 on Day 1 of Cycle1 with induction 27

28. RTOG 1333: A Randomized Phase II Trial of Lower Dose RT with or without Cisplatin in HPV+ OPC28
RANDOMIZE
Cisplatin 40 mg/m2/qwk
ELIGIBILITY
Stage
T1-2 N1-2b
T3N0-2b
< 10 pack/yr
HPV+
OPC
IMRT
60Gy
IMRT
60Gy 28

29. 29
ECOG 3311 – Phase II Randomized Trial of TORS followed by Low- or Standard-dose IMRT in Resectable p16+ Locally Advanced OPC
LOW RISK:
T1-T2N0-N1 negative margins
Observation
Assess Eligibility:
HPV (p16+) OPC
Stage III-IV: cT1-2, N1-2b
(no T1N1)
Baseline Functional/
QOL Assessment
Radiation Therapy
IMRT 50Gy/25 Fx
RANDOMIZE
INTERMEDIATE:
Close margins
< 1 mm ECS
2–4 metastatic LN
PNI
LVI
Evaluate for 2-yr PFS
Local-Regional Recurrence, Functional Outcomes/QOL
Transoral Resection (any approach)
with neck dissection
Radiation Therapy
IMRT 60 Gy/30 Fx
HIGH RISK:
Positive Margins
> 1 mm ECS or
≥ 5 metastatic LN
Radiation Therapy
IMRT 66 Gy/33 Fx +
CDDP 40 mg/m2 wkly 29

30. Conclusions Majority of OPC are now HPV 16 related
Better prognosis regardless of standard therapy applied
Specific HPV+ sub-groups do better independent of staging
Future standard treatment for these patients is undefined
Deintensification remains investigational and should not be done outside of a clinical trial
As treatment deintensification proves successful, we hope the quality of life for cured patients significantly improves

31. Thank You !!