Head and neck cancer disparities, Genetics, Environment, Behavior: What really matters?
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1 Head and neck cancer disparities, Genetics, Environment, Behavior: What really matters? Camille Ragin, PhD, MPH Associate Professor Cancer Prevention and Control Program
2 No financial relationships with commercial interests
3 Contributing Factors for Cancer Disparities Genetics/Family History e.g. Fanconi Anemia Genetic Ancestry Host Genetic polymorphisms? Healthcare access Cultural norms Environment Behavior X Diet SES HPV Educational Attainment Tobacco/Alcohol abuse
4 Head and Neck Squamous Cell Carcinoma Malignant tumors arising from, a variety of sites in the upper aerodigestive tract Lips, oral cavity, floor of mouth, top of mouth, tongue, oropharynx (throat), tonsils, salivary glands and larynx (voice box).
5 Overview Background Etiology of head and neck cancer Epidemiology of disease Racial disparity Contributing factors to survival disparity Genetics, environment, behavior: which is it??
6 ETIOLOGY
7 Causes of Head and Neck Cancer Tobacco use pipes, cigars, cigarettes, and chewing tobacco OR 42.9 for >25 cigarettes/day OR 37.2 for > 40 years of smoking Alcohol consumption OR 5.9 for > 56 drinks per week Synergistic increased risk when combined with cigarette smoking (OR 177) Talamini et al, Dec 2002 Human Papilloma Virus (20-25% HNSCC) Higher frequency in the oropharynx ~90% of HPV+ tumors carry HPV16
8 Tobacco-Associated Carcinogenesis Head Neck Mar;34(3):441-7.
9 HNSCC: Molecular Biology Its the accumulation of genetic events that deregulate cancer related genes result in tumor progression Initiation Promotion Invasion NORMAL MUCOSA 9p loss p16 INK4A HYPERPLASIA 3p, 17p loss TP53 DYSPLASIA 11q amp, 13q, 14q loss CARCINOMA in situ 6p, 8p, 4q loss CANCER CDKN2A FHIT & TP53 CCND1 Califano, J., P. et al. Cancer Res 56: (modified) Tobacco/alcohol-related
10 Karyotype Features of Tobacco-associate HNSCC 17p loss, 9p loss and 11q13 amplification are common features in Tobacco-associated HNSCC 9p loss 11q13amp 17p loss Reshmi SC, Rose Ragin C and Gollin SM: Genes Chromosomes Cancer 2004; 41:38-46
11 HPV-Associated Carcinogenesis Studies of cervical cancer show: Persistent infection leads to viral integration into human chromosomes progression to cancer E6 E7 LCR E2
12 HPV-16 Integration Detected in HNSCC CaSki UPCI:SCC090 Ragin et al. Int. J of Cancer 110, (2004)
13 HPV-Associated Carcinogenesis Cell cycle checkpoints ensure genome integrity: HPV deregulates the cell cycle p16 INK4A Duensing et al. Int. J. Cancer: 109, (2004) (modified)
14 Distinct Molecular Profile of HPV-Positive HNSCC 11q13 amplification Fluorescence in situ Hybridization Ragin et al. Br J Cancer, 2006, 95: UPCI:SCC111 HPV-negative UPCI:SCC070 HPV16-positive
15 Distinct molecular profile of HPV-positive head and neck tumors CDKN2A/p16 expression Immunohistochemistry HPV-negative/p16-negative HPV-positive/p16-positive Liu, J..Ragin, C Head and Neck 2015
16 Distinct Molecular Profile of HPV-Positive HNSCC Tobacco/Alcohol TP53 - mutated HNSCC HPV TP53 - wild-type CDKN2A/p16 - loss CDKN2A/p16 - over expressed 11q13 - ~50% amplified 11q13 - not amplified TP53 - wild-type Cervical Cancer HPV CDKN2A/p16 - over expressed Ragin et al. Br J Cancer, 2006, 95:
17 Etiological Pathways to HNSCC no 11q13 amp 11q13 amp no 11q13 amp Molecular markers Oral cavity & Larynx Oropharynx Ragin et al. J. Dental Research 2007; Feb;86(2):104-14
18 What do the statistics show? EPIDEMIOLOGY
19 Head & Neck Cancer Incidence Rates Globocan (IARC) 2008
20 Head & Neck Cancer Mortality Rates Globocan (IARC) 2008
21 Racial/Gender Disparities in HNSCC Oral Cavity & Pharynx: Age-Adjusted Rates per 100,000 Mortality Incidence *Tonsil only: Age-Adjusted Rates per 100,000 Mortality Incidence Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, , National Cancer Institute. Bethesda, MD, based on November 2013 SEER data submission, posted to the SEER web site, April 2014.
22 Racial/Gender Disparities in HNSCC *Larynx: Age-Adjusted Rates per 100,000 Mortality Incidence Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, , National Cancer Institute. Bethesda, MD, based on November 2013 SEER data submission, posted to the SEER web site, April 2014.
23 Stage Distribution at Diagnosis: Percent Percent White Americans All Males Females Oral Cavity & Pharynx 0 Localized Regional Distant Unstaged Black Americans Higher proportion of Black Americans diagnosed with more regional and distant disease Localized Regional Distant Unstaged Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, , National Cancer Institute. Bethesda, MD, based on November 2013 SEER data submission, posted to the SEER web site, April 2014.
24 Percent Stage Distribution at Diagnosis: Percent White Americans All Males Females Larynx 0 Localized Regional Distant Unstaged Higher proportion of Black Americans diagnosed with more regional and distant disease Black Americans Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, , National Cancer Institute. Bethesda, MD, based on November 2013 SEER data submission, posted to the SEER web site, April Localized Regional Distant Unstaged
25 Survival Disparity in HNSCC CONTRIBUTING FACTORS
26 Contributing Factors for Cancer Disparities Genetics/Family History e.g. Fanconi Anemia Genetic Ancestry Host Genetic polymorphisms? Healthcare access Cultural norms Environment HPV Behavior X Diet SES Educational Attainment Tobacco/Alcohol abuse
27 HPV or tobacco? BEHAVIOR HPV-related disease(oropharynx cancers)
28 Overall Survival is Better for HPV-Positive HNSCC Patients Snijders et al. (1996) Paz et al. (1997) Riethdorf et al. (1997) Koch et al. (1999) Pintos et al. (1999) Gillison et al. (2000) Sisk et al. (2000) Friesland et al. (2001) Schwartz et al. (2001) Koskinen et al. (2003) Ritchie et al. (2003) Azzimonti et al. (2004) Baez et al. (2004) Hoffman et al (2005) Kozomara et al. (2005) De Petrini et al. (2006) Licitra et al. (2006) Na et al. (2007) Reimers et al. (2007) A Combined meta HR: 0.85, 95% CI: Hazard Ratio: Death Figure 1(a) Overall survival, HPV-positive vs. HPV-negative tumors; Meta Hazard Ratio: 0.85, 95% Confidence Interval: ; Q test for heterogeneity (p value =0.206) Ragin et al. Int. J. Cancer: 121, (2007) Oropharynx: meta HR: 0.72, 95%CI:
29 Disease-Free Survival is Better for HPV-Positive HNSCC Patients Pintos et al. (1999) Mellin et al. (2000) Sisk et al. (2000) Strome et al. (2002) Li et al. (2003) Azzimonti et al. (2004) Baez et al. (2004) Wittekindt et al. (2005) Reimers et al. (2007) A Combined meta HR: 0.62, 95%CI: Hazard Ratio: Disease-Free Survival Figure 2(a) Disease-free survival, HPV-positive vs. HPV-negative tumors; Meta Hazard Ratio: 0.62, 95% Confidence Interval: ; Q test for heterogeneity (p value = 0.360) Ragin et al. Int. J. Cancer: 121, (2007) Oropharynx: meta HR: 0.51, 95% CI:
30 Variations in Prevalence of HPV+ HNSCC: Race/Geography * 148 studies Oropharynx (3,946 patients) - Any HPV: 45.8% ( ) - HPV16: 40.6% ( ) Data not disaggregated by race
31 Meta and Pooled Analysis of HPV HNSCC in Blacks PubMed (- Dec 2014) 16 Studies evaluated HPV in Black HNSCC patient tissues 910 cases Africa 4 studies (431 cases) USA 12 studies (479 cases) Ragin et al. (Manuscript in preparation)
32 Prevalence of HPV in Black Oropharynx Cancer patients Any HPV % Study ES (95% CI) Weight 7 studies (0.00, 0.05) (0.03, 0.51) 0.00 (0.00, 0.49) 0.37 (0.22, 0.54) 0.16 (0.09, 0.27) 0.31 (0.20, 0.45) Oropharynx (219 patients) - Any HPV: 24.5% ( ) - HPV16: 27.1% ( ) (0.56, 0.82) Overall (I^2 = 95.8%, p = 0.000) 0.25 (0.05, 0.44) % Study HPV 16 ES (95% CI) Weight Ndiaye et al (0.00, 0.43) 0.00 (0.00, 0.66) studies (0.00, 0.49) 0.37 (0.22, 0.54) Oropharynx (3,946 patients) - Any HPV: 45.8% ( ) - HPV16: 40.6% ( ) Overall (I^2 = 86.9%, p = 0.000) 0.35 (0.19, 0.55) 0.31 (0.20, 0.45) 0.70 (0.56, 0.82) 0.27 (0.07, 0.47)
33 Data suggest that Blacks with oropharynx cancer are less likely to be HPV+ Patients with HPV + oropharynx cancers have better survival Is poor survival in Blacks really attributed to HPV status only?
34 Overall Survival of Black Americans Survival Probability Poor survival in Blacks is not related to HPV status, rather p16 N = 44 (75% HPV +) Current/Former smokers (73%)* Non-smoker (2%) Unknown smoking status (25%) Overall 5-Year Survival Estimates P = p = HPV+ p16+ HPV+ p16- HPV+ HPV - HPV- p16- P (30) 0 P16-20 (45)* 11(25)* Survival Time in Months HPV- & p16- HPV+ & p16+ HPV+ & 2 p16- Year Survival % 5 year Survival % HPV+ & P % 64.3% HPV+ & p % 17.3% HPV- & p % 10.0% In Black Americans HPV may be a passenger and not a driver Liu, J..Ragin C. Head and Neck, 2015
35 Summary Prevalence of HPV in oropharynx cancer appear to be lower in Black Americans compared to White Americans but this may not necessarily explain the survival disparity Disparity in survival is attributed to p16 silencing rather than HPV infection possible GENETIC consequence from tobacco exposure? Further studies are needed to understand this phenomenon HPV+/p16- Black American oropharynx cancer patients
36 Tobacco-related disease SES, access to care or tobacco? ENVIRONMENT/BEHAVIOR?
37 SES/Access to Care Do differences in disease outcome remain when tumor stage, tobacco dose, SES and access to healthcare are considered simultaneously? Ragin et al. Head and neck, 2010 Oct 21. [Epub ahead of print]
38 Ragin et al. Head and neck, 2010 Oct 21. [Epub ahead of print] Black American (N = 87) White American (N = 261) 3:1 Matched: Age, Smoking dose
39 * *
40 Relapse-free Survival According to Race Irrespective of cancer site
41 Relapse-free Survival According to Race Relapse-free survival larynx tumors: Black vs. White patients AdjHR = 3.36, 95% CI: Multivariable Cox proportional hazards models (adjusting for age, race, gender, family history of cancer, alcohol use, socioeconomic status, insurance, tobacco use, stage at diagnosis, and treatment modality) Factors other than ENVIRONMENT (socioeconomic status and access to care) and BEHAVIOR (tobacco) may contribute to poor relapse-free survival No data for HPV Ragin et al. Head and neck, 2010 Oct 21. [Epub ahead of print]
42 Follow-up Studies Disparities in HNC survival Retrospective analysis: TUH/FCCC , 2,727 cases Neighborhood-deprivation, standard of care, therapy and race Analysis in progress
43 Tobacco or Host genetics? Tobacco-related cancers ENVIRONMENT/HOST(GENETICS)
44 Larynx cancer ANALYSIS Somatic mutation data of AA (13) and EA (57) patients were retrieved - Samples matched for advanced stage, age, smoking status and smoking dose -Mutational landscapes
45 * A, D, G: Unmatched B, E, H: Current/Former smokers, Age <70yrs, Stage III/IV, C, F, I: Current/Former smokers, Age <70yrs, Stage IV, Pack years (matched) * Race and age assoc. with mutation load. (adjusted: pack yrs) Manuscript in review (IJC)
46 Matched: Stage IV, cig pack-year, but frequency of G>T (tobaccorelated) differs by race Pattern of frequently mutated genes differ by race Mutation patterns of genes in one or more patients Manuscript in review (IJC)
47 Larynx cancer mutation landscape differs by race among smokers Genomic differences between Black Americans and White Americans may contribute to survival disparities? Implications for precision medicine? This investigation is ongoing
48 Head and neck cancer disparities Genetics, Environment, Behavior? Disparities in survival not as simple as we would expect ENVIRONMENT (SES and access to care) is not the only contributing factor BEHAVIOR (tobacco smoking, HPV infection) alone is not the only contributing factor Tobacco-associated disease (larynx) Possible contributions of host GENETICS HPV-associated disease (oropharynx) Possible GENETIC consequence of tobacco exposure
49 Contributing Factors for Cancer Disparities Genetics/Family History e.g. Fanconi Anemia Genetic Ancestry Host Genetic polymorphisms? Healthcare access Cultural norms Environment HPV Behavior X Diet SES Educational Attainment Tobacco/Alcohol abuse
50 The Team Ragin (FCCC, Molecular Epidemiology) Liu (TUH/FCCC, Otolaryngology) Kulathinal (TU, Genomics, Bioinformatics) Meganathan Poorlin-Ramakodi, PhD Ragin lab, FCCC
51 Ragin Lab
52
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