Environmental Tobacco Smoke (ETS) and the Risk of Head and Neck Cancer:

INHANCE Consortium

Yuan-Chin Amy LeeGene-Environmental Epidemiology Group

International Agency for Research on CancerJCCC Molecular Epidemiology Symposium, UCLA

April 14, 2007

Background Metabolites of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)

were observed in the urine of non-smokers exposed to ETS (Hecht, 2006).

About 7.5 million workers in 15 European Union countries and 24.6 million in the USA are exposed to ETS at work (Jaakkola, 2006).

ETS is modifiable by public health intervention.

ETS has not been fully investigated for head and neck cancer mainly because of the small number of cases who are never tobacco users.

Upper Respiratory Tract

The IARC Monograph concluded (Volume 83, 2004):

ETS and Lung cancer: sufficient evidence ETS and Breast cancer and other cancer

sites: inconsistent evidence

US Surgeon General’s report concluded (2006):

ETS and Lung cancer: sufficient evidence ETS and Breast cancer and nasal sinus

cancer: suggestive but not sufficient evidence

Previous Literature

Zhang et al. reported an OR of 2.4 (95% CI 0.9-6.8) for ETS and head and neck cancer risk, adjusting for age, sex, race, education, alcohol use, marijuana use, smoking (2000). However, the analysis was not restricted to never tobacco

users.

Vineis et al. reported a HR of 1.21 (0.82-1.78) for ETS and respiratory diseases (lung, pharyngeal, laryngeal cancers and other pulmonary disease), adjusting for age, sex, smoking, country and school years (2005). However, they included former smokers in the analysis.

International Head and Neck Cancer Epidemiology Consortium (http://inhance.iarc.fr)

Collaboration of research groups leading large molecular epidemiology studies of head & neck cancer.

Established in 2004 Aim to address research questions that are difficult to

evaluate in individual level studies never-tobacco users are a rare subgroup for head and neck

cancer cases since tobacco smoking accounts for the majority of cases

Data pooling projects are on-going Current pooled data includes 15 case-control studies with

~10,000 cases and 15,000 controls

Summary of Studies with ETS Data in INHANCE Pooled Data v1.0

Cases Controls Study

Location Recruitment

period Source No Never

tobacco users

Source No Never tobacco

users

Puerto Rico 1992-1995 Cancer registry 350 32

Residential records 521 211

Tampa, FL 1994-2003 Hospital 207 37

Cancer screening

clinic - healthy 897 345 Central Europe 1998-2003 Hospital 762 49

Hospital-unhealthy 907 308

South America 2000-2003 Hospital 2191 123

Hospital- unhealthy 1706 506

Los Angeles 1999-2004 Cancer registry 417 115 Neighborhood 1005 453

Houston 2001-2006 Hospital 830 186 Hospital visitors 865 374 Total 4757 542 5901 2197

Statistical Methods ETS status (never/ever), duration and frequency

variables for ETS were pooled across six studies. Subjects were asked about ETS exposure at home an

d at work

Never tobacco users: individuals who had not used cigarettes, cigars, pipes, snuff or chewing products.

Odds ratios were adjusted for centers, age, sex, race/ethnicity, education and cumulative alcohol consumption, where appropriate.

Stratified analyses were performed by cancer site, including oral cavity (n=146), pharynx (n=225), oral/pharynx NOS (n=98), and larynx (n=71).

Distribution of Demographic Characteristics among Never-Tobacco-UsersCases (%) Controls (%)

Total 542 2197Age

<40 59 (10.89) 186 (8.47)40-<45 48 (8.86) 185 (8.42)45-<50 73 (13.47) 283 (12.88)50-<55 81 (14.94) 397 (18.07)55-<60 81 (14.94) 366 (16.66)60-<65 54 (9.96) 268 (12.20)65-<70 39 (7.20) 221 (10.06)70-<75 55 (10.15) 173 (7.87)>=75 52 (9.59) 118 (5.37)P-value for chi square test <0.001

SexFemale 217 (40.04) 936 (42.60)Male 325 (59.96) 1261 (57.40)P-value for chi square test 0.278

RaceWhite 332 (61.25) 1302 (59.26)Black 20 (3.69) 137 (6.24)Hispanic 43 (7.93) 166 (7.56)Asian and pacific islander 19 (3.51) 41 (1.87)Others 5 (0.92) 45 (2.05)Latin American 123 (22.69) 506 (23.03)P-value for chi square test 0.018

Education level<=Junior High school 126 (23.77) 516 (24.26)some high school 37 (6.98) 152 (7.15)High school graduate 88 (16.60) 342 (16.08)Technical school some college 100 (18.87) 392 (18.43)>=College graduate 179 (33.77) 725 (34.09)missing 12 70P-value for chi square test 0.996

ETS at Home and the Risk of Head and Neck Cancer

*Adjusted for centers, age, sex, race/ethnicity, education and alcohol drinking

Never Tobacco Users Never Tobacco/Never Alcohol Users Ca Co OR 95 %CI Ca Co OR 95 %CI

Ever ETS exposurenever 186 794 1.00 87 409 1.00ever at home or work 303 1078 1.10 ( 0.70, 1.74) 149 487 1.30 ( 0.93, 1.80)Total 489 1872 236 896Missing 37 278 21 117p for heterogeneity

Duration of ETS exposure at homenever 184 1074 1.00 74 477 1.001-15 years 70 294 1.64 ( 0.78, 3.47) 32 103 2.04 ( 1.21, 3.43)>15 years 63 251 1.94 ( 0.94, 4.02) 36 130 1.73 ( 1.05, 2.86)Total 317 1619 142 710Missing 206 517 115 303p for heterogeneity p for trend 0.05 <.01

Frequency of ETS exposure at home0-3 hours/day 116 696 1.00 52 345 1.00>3 hours/day 15 81 1.88 ( 0.26, 13.62) 5 20 1.00 ( 0.89,15.09)Total 131 777 57 365Missing 398 1381 200 648p for heterogeneity

ETS at Work and the Risk of Head and Neck Cancer

*Adjusted for centers, age, sex, race/ethnicity, education and alcohol drinking

Never Tobacco Users Never Tobacco/Never Alcohol Users Ca Co OR 95 %CI Ca Co OR 95 %CI

Duration of ETS exposure at worknever 174 898 1.00 75 446 1.001-15 years 54 309 0.89 ( 0.47, 1.68) 19 105 1.14 ( 0.62, 2.11)>15 years 35 128 1.80 ( 0.81, 4.02) 11 35 2.35 ( 1.04, 5.29)Total 263 1335 105 586Missing 264 818 152 427p for heterogeneity p for trend 0.18 0.07

Frequency of ETS exposure at worknever 107 499 1.00 50 239 1.001-3 hours/day 19 112 1.16 ( 0.00,622.8) 7 24 1.88 ( 0.66, 5.40)>3 hours/day 30 132 1.14 ( 0.04,32.46) 9 41 1.24 ( 0.50, 3.06)Total 156 743 66 304Missing 373 1408 191 709p for heterogeneity p for trend 0.67 0.47

ETS and the Risk of Oral, Pharyngeal and Laryngeal Cancers among Never Tobacco Users

*Adjusted for centers, age, sex, race/ethnicity, education and alcohol drinking

Oral Pharynx Larynx Ca Co OR 95 %CI Ca Co OR 95 %CI Ca Co OR 95 %CI

Ever ETS exposurenever 53 794 1.00 72 794 1.00 23 794 1.00ever at home or work 76 1078 0.93 ( 0.61, 1.41) 135 1078 0.94 ( 0.67, 1.33) 45 1078 1.69 ( 0.97, 2.97)Missing 11 278 14 278 0 67p for heterogeneity 0.58 <.01 0.34

Duration of ETS exposure at homenever 46 1074 1.00 53 1074 1.00 36 938 1.001-15 years 12 294 1.55 ( 0.71, 3.35) 27 294 1.37 ( 0.80, 2.36) 8 278 1.45 ( 0.59, 3.56)>15 years 16 251 1.02 ( 0.51, 2.03) 16 251 2.12 ( 1.13, 4.00) 15 221 2.60 ( 1.21, 5.61)Missing 64 517 124 517 10 502p for heterogeneity 0.26 0.26 0.84 p for trend 0.79 0.02 0.02

Duration of ETS exposure at worknever 46 898 1.00 48 898 1.00 34 898 1.001-15 years 9 309 0.72 ( 0.31, 1.65) 19 309 0.75 ( 0.41, 1.37) 9 309 0.98 ( 0.43, 2.23)>15 years 7 128 1.14 ( 0.43, 3.01) 9 128 1.81 ( 0.79, 4.19) 15 128 2.29 ( 1.10, 4.78)Missing 78 818 145 818 10 607p for heterogeneity 0.97 0.04 0.80 p for trend 0.92 0.60 0.05

Oral Pharynx Larynx Ca Co OR 95 %CI Ca Co OR 95 %CI Ca Co OR 95 %CI

Ever ETS exposurenever 32 409 1.00 28 409 1.00 8 409 1.00ever at home or work 51 487 1.16 ( 0.67, 1.99) 57 487 1.32 ( 0.78, 2.25) 18 487 2.89 ( 1.09, 7.71)p for heterogeneity 0.69 0.52

never 26 477 1.00 14 477 1.00 13 421 1.001-15 years 8 103 2.25 ( 0.83, 6.07) 8 103 2.88 ( 1.04, 7.96) 3 98 2.03 ( 0.44, 9.45)>15 years 10 130 1.27 ( 0.53, 3.05) 9 130 4.04 ( 1.47,11.11) 7 116 1.80 ( 0.52, 6.16)p for heterogeneity 0.22 0.54 0.62 p for trend 0.44 <.01 0.28

never 25 446 1.00 15 446 1.00 12 446 1.001-15 years 5 105 1.08 ( 0.33, 3.58) 3 105 0.76 ( 0.19, 3.00) 4 105 2.85 ( 0.72,11.28)>15 years 2 35 1.64 ( 0.28, 9.56) 2 35 3.61 ( 0.62,21.03) 6 35 5.91 ( 1.56,22.33)p for heterogeneity 0.81 0.14 0.41 p for trend 0.63 0.44 <.01

Duration of ETS exposure at home

Duration of ETS exposure at work

ETS and the Risk of Oral, Pharyngeal and Laryngeal Cancers among Never Tobacco/Never Alcohol Users

*Adjusted for centers, age, sex, race/ethnicity, and education

Studies on ETS, Genetic Variants and Cancer

Studies with SNPs of Metabolic Genes

StudyADH1C I350V

CYP1A1 I462V

CYP2E1 1143AT

CYP2E1 1293GC

CYP2E1 1054CT GSTM1

GSTM3 3bpdel,

Mnl IGSTP1 A114V

GSTP1 I105V GSTT1

NQO1 P187S

Houston, TX x x x x x x xCentral Europe x x x x x x x xSouth America

Los Angeles, CA x x x x xTampa, FL

Puerto Rico x x x x x xNo of studies with SNP data 3 3 0 2 0 4 1 2 4 4 3

SNPs of Metabolic Genes Stratified ETS Status for Head and Neck CancerAll Ever ETS Never ETSCa Co OR 95 %CI Ca Co OR 95 %CI Ca Co OR 95 %CI

gstp1_i105vIle/Ile 127 445 1.00 77 269 1.00 43 143 1.00Ile/Val 152 470 1.08 ( 0.81, 1.44) 93 293 1.08 ( 0.74, 1.56) 54 159 1.12 ( 0.66, 1.91)Val/Val 32 110 0.93 ( 0.58, 1.48) 22 68 1.11 ( 0.62, 1.99) 8 36 0.61 ( 0.24, 1.57)Missing 218 1138 112 456 84 465p for heterogeneity 0.29 0.36 0.17 p for trend 0.98 0.67 0.60 nqo1_p187s Pro/Pro 124 487 1.00 85 322 1.00 39 165 1.00Pro/Ser 70 285 0.93 ( 0.66, 1.32) 47 191 0.95 ( 0.62, 1.47) 23 94 1.01 ( 0.53, 1.95)Ser/Ser 14 35 1.63 ( 0.81, 3.27) 6 21 0.96 ( 0.34, 2.72) 8 14 2.54 ( 0.86, 7.49)Missing 322 1361 166 553 119 530p for heterogeneity 0.29 0.52 0.03 p for trend 0.57 0.84 0.24 cyp1a1_i462v Ile/Ile 96 466 1.00 51 275 1.00 39 172 1.00Ile/Val 10 57 0.84 ( 0.38, 1.84) 4 28 0.75 ( 0.22, 2.50) 6 27 1.29 ( 0.38, 4.32)Val/Val 4 13 1.75 ( 0.48, 6.46) 4 5 3.37 ( 0.70,16.32) 0 0Missing 420 1628 245 778 144 596p for heterogeneity 0.68 0.37 0.50 p for trend 0.76 0.35 0.88 gstt1_null present 244 773 1.00 153 476 1.00 82 260 1.00null 62 233 0.80 ( 0.57, 1.12) 38 141 0.77 ( 0.50, 1.18) 19 71 0.87 ( 0.46, 1.61)Missing 224 1159 114 470 88 473p for heterogeneity 0.79 0.58 0.13 gstm1_null present 151 483 1.00 89 281 1.00 53 171 1.00null 154 511 0.98 ( 0.75, 1.29) 102 329 1.05 ( 0.74, 1.50) 47 155 1.09 ( 0.65, 1.83)Missing 225 1171 114 477 89 478p for heterogeneity 0.45 0.68 0.81

*Adjusted for centers, age, sex, race/ethnicity, education and alcohol drinking

Limitations & Strengths

Limitations Comparability of ETS

variables

Recall bias

Limited information on SNPs

Strengths Restriction to never

tobacco users

More statistical power

Stratification by site

Summary I No association was observed for oral cancer.

For pharyngeal cancer, we only observed an association with >15 years of ETS at home.

For laryngeal cancer, we observed a dose-response trend in duration of ETS exposure at home and at work.

Active smoking is thought to be a stronger risk factor for laryngeal cancer than pharyngeal and oral cancer. Perhaps ETS is also a stronger risk factor for laryngeal cancer.

Summary II

We did not observe ETS modifying the effect of metabolic SNPs examined on the risk of head and neck cancer overall.

If the effect of both ETS and genetic variants is moderate, the interaction may be moderate, which is difficult to detect.

Acknowledgements

Investigators who have provided data: Curado MP, Daudt AW, Fabianova E, Wünsch-Filho V, Hayes R,

Koifman S, Lazarus P, Mates D, Matos E, Menezes A, Muscat J, Eluf-Neto J, Rudnai P, Sturgis EM, Szeszenia-Dabrowska N, Wei QY, Zaridze D, Zatonski W, Zhang ZF

Study participants

IARC: Mia Hashibe, Paolo Boffetta, Paul Brennan, Julien Berthiller,

Manuela Marron, Gilles Ferro

Support from US NCI grant (R03 CA113157)

Thank You!

ETS Variables Available by Study

Study Ever ETS Ever at home Ever at work Duration (years)

Freqency (hours/day)

Duration (years)

Frequency (hours/day)

Central Europe x x x x x x xTampa, USA x x x x x x N/APuerto Rico N/A x N/A x N/A N/A N/ASouth America x x x x x x xLos Angeles x x x x N/A x N/AHouston x x x N/A N/A N/A N/A

Ever status ETS at home ETS at work

Definitions of Never Tobacco User

Cigarette Ever pipe Ever cigar Ever snuff Ever chew

Central Europe ≥100 cigarettes Ever regularly Ever regularly - -

Tampa, USA1 cig/day for 1 year(≥ 365 cigarettes) Once a day for 1 year Once a day for 1 year Once a day for 1 year Once a day for 1 year

Puerto Rico ≥100 cigarettesEver smoke for >6months

Ever smoke for >6months

Ever chew for >6months

Ever snuff for >6months

South America1 cig/day for 1 year(≥ 365 cigarettes) 1 daily for >1 year 1 daily for >1 year - -

Los Angeles ≥100 cigarettes1 per month for >6months

1 per month for >6months

1 plug per month for>6 months

1 pinch per month for>6 months

Houston ≥100 cigarettes Ever smoke Ever smoke Ever use Ever use