1. Pathophysiology and Molecular Features of HPV-associated head and neck cancer
Eddy S. Yang, MD, PhD
Professor and Vice Chair of Translational Sciences
Department of Radiation Oncology
University of Alabama at Birmingham (UAB) Comprehensive Cancer Center

2. Disclosures Research support from Eli Lilly, Bayer, Janssen, Tesaro
Advisory Board Strata Oncology
Consultant Nanostring Technologies

3. Objectives
To compare outcomes between HPV-associated and non-HPV- associated head and neck cancer
To review new AJCC staging guidelines for HPV+ oropharynx
To review the etiology of HPV-associated head and neck cancer
To discuss the molecular features of HPV-associated head and neck cancer

4. HPV+ HNSCC is rising
Chaturvedi et al. JCO :

5. HPV status and Survival – RTOG 0129
Retrospective analysis of OS and PFS:
3 yr OS: 82% HPV+, 57% HPV-
3 yr PFS: 73% HPV+, 43% HPV-
3 yr LRR: 13.6% HPV+, 35% HPV-
No diff in distant metastasis
Better outcomes in HPV + disease
Ang KK et al. NEJM 2010

6. HPV status and Survival – RTOG 0522
Correlative analysis of OS, PFS, and DM:
3 yr OS: 86% HPV+, 60% HPV-
3 yr PFS: 73% HPV+, 49% HPV-
3 yr DM: 6.5% HPV+, 17% HPV-
3 yr LRF: 17% HPV+, 33% HPV-
Better outcomes in HPV + disease
Ang KK et al. NEJM 2010

7. Risk Stratification for HNSCC patients90 70 45
Retrospective analysis and RPA of RTOG 0129 showing prognostic groups based on HPV status, T stage, N stage, and pack years
Solid lines in the graph are the Kaplam Myer curves. Lighter ones are the 95% confidence interval curves.
266 pts chosen where HPV status and smoking hx known. All were OPX
Ang KK et al. NEJM 2010

8. HPV status and survival after progression
Fakhry et al. JCO 2014

9. Dose de-escalation for HPV+ HNSCC
Stage III/IV HPV+ HNSCC patients
Induction cis, paclitaxel, cet
Primary site cCR
IMRT 54Gy + weekly cet
Primary site < cCR
IMRT 69.3Gy + weekly cet
Further studies needed
Marur et al. JCO 2016

10. New staging system needed for HPV+88 82 84 81 60 76 68 53 45 34
O’Sullivan et al. Lancet Oncology 2016

11. New staging – HPV+ oropharynx
Nodal Status
7th Edition AJCC Staging
ICON-S
None N0
Unilateral
N1, N2a, N2b N1
Contra/Bilateral
N2c N2
>6cm N3
O’Sullivan et al. Lancet Oncology 2016

12. AJCC 8th ed. (2017) Oropharynx: pN stage in HPV+ disease
Now related to number of LN’s and not to size.
Neither LN size nor contralateral involvement conveyed greater survival
if treated with surgery in comparison to being treated with RT.
HPV+ pN stage now based on number of + LN’s

13. HPV oncogenesis p53 P16-CDK2/4-Rb
Moody & Laimins Used with permission

14. DNA damage response
Jackson & Bartek Used with permission

15. DNA Double Strand Break Repair
Homologous recombination repair
BRCA1/BRCA2
Rad51
Nonhomologous end-joining repair
53BP1
Ku70/80
DNA-PK

16. HPV+ HNSCCs have delayed resolution of IR-induced DNA DSBs
Weaver et al. Oncotarget 2015

17. HPV+ HNSCCs harbor defects in NHEJ repair signaling
Weaver et al. Oncotarget 2015

18. HPV+ HNSCCs display defects in HR repair signaling
Weaver et al. Oncotarget 2015

19. HPV+ HNSCCs display defects in HR repair signaling
Weaver et al. Oncotarget 2015

20. HPV+ HNSCCs are sensitive to PARP inhibition in vivo
Weaver et al. Oncotarget 2015

21. Genomic insights HPV+ HNSCC
DNA alterations
PIK3CA
TRAF3
E2F
FGFR3
Gene expression
miRNA
lncRNA
TCGA Nature 2015

22. lncRNAome
Nohata et al. Oral Oncology 2016

23. Summary and Conclusions
Incidence and prevalence of HPV-associated HNSCCs are rising
Better prognosis
Dose de-escalation
Biologically different – DNA repair defect/other targets

24. Thank you

25. AJCC 8th ed. (2017) Oropharynx: T stage
Oral cavity, larynx, hypopharynx, and Para-nasal Sinus
use the same.
Oropharynx: T stage
T categories remained the same given they were found to be equally valid in a prognostic standpoint but there were 2 main changes in the HR-HPV+ : No Tis (In situ stage) due to non aggressive pattern in invasive disease, T4b status eliminated.
The HPV – stage is used also for OC, HPX, Sinuses.
T0 was eliminated of all HN sites except for NPX, +HPV OPX, salivary gland cancers and UNKNOWN PRIMARY (without site)
“B”Mucosal extension to lingual surface of epiglottis
from primary tumors of the base of the tongue and vallecula does not constitute
invasion of the larynx.

26. AJCC 8th ed. (2017) Oropharynx : cN stage
*** For clinical ENE+: Physical examination (invasion of skin,
infiltration of musculature/dense tetheringto adjacent structures,
or dysfunction of a cranial nerve,
the brachial plexus, the sympathetic trunk, or the phrenic
nerve) and supported by radiological evidence needed.
HPV + : N1 now includes up to 6cm unilateral; N2: other side; N3: >6cm
HPV -: Involved the presence of ECE in the staging system. All remained the same but for N3 divided to a and b. ( B being presence of ENE)

27. AJCC 8th ed. (2017) Pathologic N Stage (pN)
** Upstaging by ENE+ status
Therefore, for clinical staging, only
unambiguous ENE, as determined by physical examination
(eg, invasion of skin, infiltration of musculature/dense tethering
to adjacent structures, or dysfunction of a cranial nerve,
the brachial plexus, the sympathetic trunk, or the phrenic
nerve) and supported by radiological evidence, should be
present to assign a status of ENE-positive.
Pathological ENE is defined as extension of metastatic
carcinoma from within a lymph node through the fibrous
capsule and into the surrounding connective tissue, regardless
of the presence of stromal reaction.

28. AJCC 8th ed. (2017)
No Stage IV Subdivision