Cancer and its Causes in Korea

Transcription

1 Cancer and its Causes in Korea Prof. Dr. David Khayat, MD, PhD Former Head of Medical Oncology at Pitié-Salpêtrière in Paris Former President of the National Cancer Institute in France Harm Reduction Consultant to PMI

2 Agenda Burden of Non-Communicable Diseases Causes of cancer in Korea Cancer development - a matter of dose and response How does cigarette smoke cause cancer Smoking Prevalence Globally and in Korea Or why better, less harmful alternatives are needed 2

3 The Burden of Non-Communicable Diseases 3

4 The Burden of Non-Communicable Diseases (NCDs) Global Burden of NCDs NCDs such as Cardiovascular, Respiratory Disease and Cancer cause: > 39 Mio Death globally in 2016 ~ 9 Mio cancer deaths in 2016 NCD Burden in Korea NCDs such as Cardiovascular, Respiratory Disease and Cancer cause: > 284k death in 2016 > 100k cancer deaths in 2016 Numbers are based on public statistics for Korea Source: Institute for Health Metrics and Evaluation (IHME). GBD Compare Data Visualization. Seattle, WA: IHME, University of Washington, Available from vizhub.healthdata.org/gbd-compare. (Accessed August 8 th 2018) 4

5 Causes of Cancer in Korea 5

6 Risk Factors for Cancer in Korea Korea, All Ages, Both Sexes, Deaths per 100, rank 2016 rank 1 Smoking 1 Smoking 2 Alcohol Use 2 Alcohol Use 3 High Body Mass Index 3 High Fasting Plasma Glucose 4 Diet High in Sodium 4 High Body Mass Index 5 Diet Low in Fruits 6 Unsafe Sex 7 High Fasting Plasma Glucose 5 Ambient Particulate Matter Pollution 6 Diet High in Sodium 7 Diet Low in Fruits 8 Ambient Particulate Matter Pollution 8 Diet Low in Milk Numbers are based on public statistics for Korea Rank Diet High in Red Meat Rank Diet High in Red Meat Rank Source: Institute for Health Metrics and Evaluation (IHME). GBD Compare Data Visualization. Seattle, WA: IHME, University of Washington, Available from vizhub.healthdata.org/gbd-compare. (Accessed August 8 th 2018) 6

7 Cancer development - a matter of dose response 7

8 Events in Carcinogenesis Carcinogenesis Initiation Phase (1 ~ 2 days) Carcinogenesis Promotion Phase (10 ~ 20 years) Carcinogenesis Progression Phase (> 1 year) Genetic damage Tumor Promoting Environment Modified cells (Hyperplasia) appear Adenomas appear Carcinomas appear 8

9 Dose Response What is there that is not poison? All things are poison and nothing is without poison. Solely the dose determines that a thing is not a poison. Paracelsus 9

10 Exposure Outside the body Dose Response Dose Inside the body Response Change in structure or function Source Host Adverse Health Effect Air, Food, Consumables Humans Disease 10

11 RESPONSE Types of Dose Response 100% Non-Carcinogens Carcinogens 0% Low Dose Exposure DOSE The schematic presented here illustrates that the lower the dose, the more reduced is the response and therefore the risk associated with the response Adapted from: Principles of Exposure, Dose, and Response; The Johns Hopkins University,

12 Food: Colorectal Cancer Risk (CRC) CRC Risk through intake of red and processed meat CRC risk through intake of Fish Points in the figure represent median intakes in each category of consumption. Curves generated from calibrated data (solid line) and uncalibrated data ( hatched line ) and upper and lower confidence intervals for calibrated data ( dotted lines ) are shown. Source: Norat, T; Meat, Fish, and Colorectal Cancer Risk: The European Prospective Investigation into Cancer and Nutrition DOI: /jnci/dji164 Journal of the National Cancer Institute, Vol. 97, No. 12, 12

13 Food: Colorectal Cancer Risk (CRC) Red meat is classified as probably carcinogenic and processed meats as carcinogenic to humans. 1 WCRF/AICR recommendation: Limit red meat consumption to 43 g/day, for cancer prevention. 2 So Young Kim however showed that an intake of 43 g / day of red meat 4 lead to an increase in cancer risk in Korea Average consumption in Korea: ~ g/day of red meat. 3 1 International Agency for Research on Cancer (IARC); Bouvard, V.; Loomis, D.; Guyton, K.Z.; Grosse, Y.; Ghissassi, F.E.; Benbrahim-Tallaa, L.; Guha, N.; Mattock, H.; Straif, K. Carcinogenicity of consumption of red and processed meat. Lancet Oncol. 2015, 16, World Cancer Research Fund and American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective; American Institute for Cancer Research (AICR): Arlington, VA, USA, Korea National Health and Nutrition Examination Survey (KNHANES). Available online: 4 Kim, SY; The Role of Red Meat and Flavonoid Consumption on Cancer Prevention: The Korean Cancer Screening Examination Cohort; Nutrients 2017, 9, 938; doi: /nu

14 Odd Ratio Smoking: Lung Cancer Years of Cigarette Smoking Cigarette Smoking and Lung Cancer: Modeling Total Exposure and Intensity; Jay H. Lubin and Neil E. Caporaso; Cancer Epidemiol Biomarkers Prev March (15) (3) ; DOI: / EPI

15 How does cigarette smoke cause cancer? 15

16 Carcinogens in Cigarette Smoke Tobacco smoke contains more than 6000 chemicals as well as solid ultrafine particles of them have been listed by the FDA as Harmful and Potentially Harmful Constituents (HPHCs). 2 The majority are classified as carcinogens or potential carcinogens. 2 1 Rodgman A, Perfetti TA. The chemical components of tobacco and tobacco smoke 2nd ed: CRC Press, Taylor & Francis Inc (United States); Reporting Harmful and Potentially Harmful Constituents in Tobacco Products and Tobacco Smoke Under Section 904(a)(3) of the Federal Food, Drug, and Cosmetic Act; 16

17 Understanding Cancer Potency of Carcinogens* Carcinogens Compound IARC Class Tobacco Smoke (n=309) Mean Concentration (μg/ml) Heat-Not-Burn (n=44) E-Cigarettes (n=44) Nicotine Inhaler (n=1) % Reduction* % Reduction* % Reduction* Acrylonitrile 2B % NR 99.8% 1,3 - Butadiene % NR 99.9% BDL: Below detection limit; NR: Not reported * compared to Tobacco Smoke * Based on :Stephens WE; Comparing the cancer potencies of emissions from vapourised nicotine products including e-cigarettes with those of tobacco smoke; Tobacco Control Published Online First: 04 August doi: /tobaccocontrol

18 Understanding Cancer Potency of Carcinogens* Carcinogens Compound IARC Class Tobacco Smoke (n=309) Mean Concentration (μg/ml) Heat-Not-Burn (n=44) E-Cigarettes (n=44) Nicotine Inhaler (n=1) % Reduction* % Reduction* % Reduction* Acrylonitrile 2B % NR 99.8% 1,3 - Butadiene % NR 99.9% Acetaldehyde 2B % 99.8% NR BDL: Below detection limit; NR: Not reported * compared to Tobacco Smoke * Based on :Stephens WE; Comparing the cancer potencies of emissions from vapourised nicotine products including e-cigarettes with those of tobacco smoke; Tobacco Control Published Online First: 04 August doi: /tobaccocontrol

19 Understanding Cancer Potency of Carcinogens* Carcinogens Compound IARC Class Tobacco Smoke (n=309) Mean Concentration (μg/ml) Heat-Not-Burn (n=44) E-Cigarettes (n=44) Nicotine Inhaler (n=1) % Reduction* % Reduction* % Reduction* Acrylonitrile 2B % NR 99.8% 1,3 - Butadiene % NR 99.9% Acetaldehyde 2B % 99.8% NR Formaldehyde % 94.7% NR Cadmium BDL 94.9% 99.5% BDL: Below detection limit; NR: Not reported * compared to Tobacco Smoke * Based on :Stephens WE; Comparing the cancer potencies of emissions from vapourised nicotine products including e-cigarettes with those of tobacco smoke; Tobacco Control Published Online First: 04 August doi: /tobaccocontrol

20 Understanding Cancer Potency of Carcinogens* Carcinogens Compound IARC Class Tobacco Smoke (n=309) Mean Concentration (μg/ml) Heat-Not-Burn (n=44) E-Cigarettes (n=44) Nicotine Inhaler (n=1) % Reduction* % Reduction* % Reduction* Acrylonitrile 2B % NR 99.8% 1,3 - Butadiene % NR 99.9% Acetaldehyde 2B % 99.8% NR Formaldehyde % 94.8% NR Cadmium BDL 94.9% 99.5% TSNA - NNN % 99.96% BDL TSNA - NNK % 99.7% BDL Mean Life Time Cancer Risk* BDL: Below detection limit; NR: Not reported * compared to Tobacco Smoke * Based on :Stephens WE; Comparing the cancer potencies of emissions from vapourised nicotine products including e-cigarettes with those of tobacco smoke; Tobacco Control Published Online First: 04 August doi: /tobaccocontrol

21 Cancer Potency of Carcinogens of Nicotine and Tobacco Containing Products Based on: Stephens WE; Comparing the cancer potencies of emissions from vapourised nicotine products including e-cigarettes with those of tobacco smoke; Tobacco Control Published Online First: 04 August doi: /tobaccocontrol

22 % of Reference Cigarette Example: FDA Study on IQOS Emissions 100% 0 Cigarette 80% 20 60% 40 >90% >90% >80% >92% >98% 40% 60 20% 80 0% 100 Acrolein B[a]P Formaldehyde NNN NNK Note: Intense Health Canada s Smoking Regime; Comparison on a per-stick basis; Excludes Nicotine, Glycerin and Total Particulate Matter Source: FDA Briefing Book for TPSAC, Page 12 as accessed at 22

23 How Cigarette Smoke Causes Cancer? Genetic damage the match that lights the fire * Toxic Cigarette Emissions Inflammation fuel that feeds the flames * Carcinogens Solid Ultrafine Particles** HPHCs Tumor initiation Cancer Tumor progression & Invasiveness*** * Balkwill F and Mantovani A. Inflammation and cancer: back to Virchow? Lancet, 2001, 357: ** You et al. Nanoparticulate carbon black in cigarette smoke induces DNA cleavage and Th17-mediated emphysema. elife 2015; 4:e09623 *** Rothwell et al. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 2011; 377:

24 How Smoking Cessation Decreases Cancer Risk Genetic damage the match that lights the fire * Inflammation fuel that feeds the flames * Carcinogens Smoking Cessation 1. Reduces Genetic damage 2. Reduces Inflammation Reduces the risk of lung cancer Solid Ultrafine Particles** HPHCs Tumor initiation Cancer Tumor progression & Invasiveness*** * Balkwill F and Mantovani A. Inflammation and cancer: back to Virchow? Lancet, 2001, 357: ** You et al. Nanoparticulate carbon black in cigarette smoke induces DNA cleavage and Th17-mediated emphysema. elife 2015; 4:e09623 *** Rothwell et al. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 2011; 377:

25 How Much Can ENDS Reduce Cancer Risk? Genetic damage the match that lights the fire *? ENDS +? Inflammation fuel that feeds the flames * Carcinogens Questions By how much can alternative products:? 1. Reduce Genetic damage? 2. Reduce Inflammation? 3. Reduce the risk of lung cancer? Solid Ultrafine Particles** HPHCs Tumor initiation Cancer Tumor progression & Invasiveness*** * Balkwill F and Mantovani A. Inflammation and cancer: back to Virchow? Lancet, 2001, 357: ** You et al. Nanoparticulate carbon black in cigarette smoke induces DNA cleavage and Th17-mediated emphysema. elife 2015; 4:e09623 *** Rothwell et al. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 2011; 377: Electronic Nicotine Delivery Systems. 25

26 Smoking Prevalence Globally and in Korea Why less harmful alternatives are needed 26

27 People will continue to smoke Worldwide it is estimated that more than 1 billion people will continue to smoke in the foreseeable future. 1 According to the ACS more than 46,700 death are attributable to smoking-related diseases every year in Korea. 2 More than 18% of the population (~33% of males) continue to smoke cigarettes in Korea American Cancer Society: 3 OECD Health Statistic 2018, as accessed on August 28 th

28 Emerging Smoke-Free Regulatory Trends new product innovations could make a lot of sense and help people transfer off cigarettes - Scott Gottlieb, Commissioner Food & Drug Administration help people to quit smoking by permitting innovative technologies that minimise the risk of harm / maximise the availability of safer alternatives to smoking heat-not-burn, snus, moist snuff, dissolvable and inhaled nicotine may be significantly safer than cigarettes. - Nicky Wagner, Former Associate Health Minister Growing number of countries are recognizing the benefit of novel smoke-free products 28

29 Scientific Update PMI s Evidence on IQOS related to Cancer Prof. Manuel C. Peitsch PMI Chief Scientific Officer

30 Agenda Totality of Evidence on IQOS to date Can switching to IQOS reduce genetic damage, inflammation? Can switching to IQOS reduce the risk of lung cancer? 30

31 Totality of Evidence on IQOS Toxic Cigarette Emissions Exposure Molecular changes Disruption of biological Mechanisms Cell/Tissue Changes Disease Population Harm Reduced Emissions Reduced Exposure Reduced Adverse Health Effects PMI 18 Non-Clinical Studies and 10 Clinical Studies 31

32 Reduced Formation: by Disease Category Toxic Cigarette Emissions Exposure Molecular changes Disruption of biological Mechanisms Cell/Tissue Changes Disease Population Harm Reduced Emissions Reduced Exposure Reduced Adverse Health Effects PMI Reduced Emissions of Exposure Reduction Harmful Chemicals in IQOS users Carcinomas in 18 Non-Clinical Studies and 10 Clinical Studies No solid ultrafine particles (PM 2.5) Effect on By- Standers Incidence of Lung animal model significantly reduced 32

33 How Cigarette Smoke Causes Cancer? Genetic damage the match that lights the fire * Inflammation fuel that feeds the flames * Carcinogens Questions Does switching from cigarettes to IQOS 1. Reduce Genetic damage? 2. Reduce Inflammation? 3. Reduce the risk of lung cancer? Solid Ultrafine Particles** HPHCs Tumor initiation Cancer Tumor progression & Invasiveness*** * Balkwill F and Mantovani A. Inflammation and cancer: back to Virchow? Lancet, 2001, 357: ** You et al. Nanoparticulate carbon black in cigarette smoke induces DNA cleavage and Th17-mediated emphysema. elife 2015; 4:e09623 *** Rothwell et al. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 2011; 377:

34 Genetic Damage is Reduced by IQOS Does Switching to IQOS Reduce Genetic damage? Genetic damage the match that lights the fire * Evidence from IQOS Assessment Reduced Emission of Carcinogens Carcinogens Reduced Exposure to Carcinogens Reduced Genotoxicity Reduced DNA Damage Tumor initiation Reduced Exposure Response Reduced Genetic Damage * Balkwill F and Mantovani A. Inflammation and cancer: back to Virchow? Lancet, 2001, 357:

35 % of Reference Cigarette Levels of Harmful Chemicals Significantly Reduced For IQOS Average reductions in emission of harmful or potentially harmful constituents for IQOS compared to levels measured in smoke from the 3R4F reference cigarette by disease category * 100% Reference Cigarette 75% 50% 25% 0% KFDA s analysis of the HNB aerosol also confirmed the on average 90% lower levels of harmful chemicals in the HNB > 95% reduction WHO (9 chemicals) > 90% reduction FDA (18 chemicals) 95% reduction Health Canada (44 chemicals) > 90% reduction PMI (58 chemicals) > 95% reduction aerosol compared to cigarette smoke. Carcinogens (15 chemicals) IQOS Platform 1 * Aerosol collection with Intense Health Canada s Smoking Regime (55 ml puff volume, 2 second puff duration, 30 second interval puff); Comparison on a per-stick basis Reduction calculations exclude Nicotine, Glycerin and Total Particulate Matter The PMI 58 list includes the FDA 18,and the 15 carcinogens of the IARC Groups 1 35

36 P e r c e n t o f C i g a r e t t e E x p o s u r e Reduced Exposure To Carcinogens IQOS Smoking Abstinence Cigarettes 8 0 Acrylonitrile 1, 3-Butadiene o - t o l 1 - O H P 3 - H P M A T o t a l H E M A H M P M A C O H b B [ a ] P 4 - A B P C E M A N N N 2 - N A S - P M A M H B M A 1 - N A N N A L The highest-ranking carcinogens for cigarettes are 1,3-butadiene and acrylonitrile, accounting for more than three-quarters of the cancer potency.. Stephens WE; Comparing the cancer potencies of emissions from vapourised nicotine products including e-cigarettes with those of tobacco smoke; Tobacco Control Published Online First: 04 August doi: /tobaccocontrol

37 Genetic Damage is Reduced by IQOS Note: the switch to IQOS and Switch to cessation study groups were exposed for 2 month to 3R4F cigarette smoke prior to being switched. Cigarette Switch to IQOS Switch to Cessation IQOS Source: Phillips B, Veljkovic E, Boué S, et al. An 8-Month Systems Toxicology Inhalation/Cessation Study in Apoe / Mice to Investigate Cardiovascular and Respiratory Exposure Effects of a Candidate Modified Risk Tobacco Product, THS 2.2, Compared With Conventional Cigarettes. Toxicological Sciences. 2016;149(2): doi: /toxsci/kfv

38 Evidence from IQOS Assessment Inflammation is Reduced by IQOS Reduced Emission of HPHCs and No Solid Ultrafine Particles Does Switching to IQOS Reduce Inflammation? Inflammation fuel that feeds the flames * Reduced Exposure to HPHCs No Exposure to Solid Ultrafine Particles Solid Ultrafine Particles** HPHCs Reduced Lung Inflammation Reduced Inflammation Tumor progression & Invasiveness*** * Balkwill F and Mantovani A. Inflammation and cancer: back to Virchow? Lancet, 2001, 357: ** You et al. Nanoparticulate carbon black in cigarette smoke induces DNA cleavage and Th17-mediated emphysema. elife 2015; 4:e09623 *** Rothwell et al. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 2011; 377:

39 Solid Ultrafine Particle Deposition in the Lung Cigarette Smoke Solid Ultrafine Particles 6x10 11 particles ~= 0.7 mg* IQOS Aerosol No Solid Ultrafine Particles Lung Deposition after 6 months Cigarette smoke* IQOS aerosol* * Corresponding nicotine concentrations Apoe-/- mice exposed for 6 months, 3h/day and 5days/week. You et al. Nanoparticulate carbon black in cigarette smoke induces DNA cleavage and Th17-mediated emphysema. elife 2015; 4:e

40 T L y m p h o c y t e C o u n t ( 1 0 5, m e a n S E M ) N e u t r o p h i l C o u n t ( 1 0 5, m e a n S E M ) T o t a l C e l l C o u n t ( 1 0 5, m e a n ± S E M ) M M P a c t i v i t y ( m U / m l, m e a n S E M ) No Lung Inflammation in IQOS Exposed Mice Total Cell Count in BALF MMP Activity in BALF M o n t h 1 * * 3 0 * * M o n t h 5 6 M o n t h 1 M o n t h * * 4 * * p < ( v s S h a m ) * * p < ( v s S h a m ) # # p < ( v s 3 R 4 F ) 1 0 # # p < ( v s 3 R 4 F ) 2 # # # # # # # # # # # # # # # # # # 0 0 A i r 3 R 4 F I Q O S I Q O S I Q O S A i r 3 R 4 F I Q O S I Q O S I Q O S L o w M e d H i g h L o w M e d H i g h T-Lymphocyte Count in BALF Neutrophil Count in BALF 3 M o n t h * * * * M o n t h 5 9 M o n t h 1 M o n t h 5 2 * * 8 * * 7 6 * * p < ( v s S h a m ) 1 # # # # p < ( v s 3 R 4 F ) * * p < ( v s S h a m ) # # p < ( v s 3 R 4 F ) # # # # # # # # # # # # # # # # # # # # # # A i r 3 R 4 F I Q O S I Q O S I Q O S A i r 3 R 4 F I Q O S I Q O S I Q O S L o w M e d H i g h Source: PMI Study Report of Study - Study number L o w M e d H i g h 40

41 How Cigarette Smoke Causes Cancer? Genetic damage the match that lights the fire * Inflammation fuel that feeds the flames * Carcinogens Tumor initiation Questions Does switching from cigarettes to IQOS 1. Reduce Genetic damage? 2. Reduce Inflammation? 3. Reduce the risk of lung cancer? Cancer Solid Ultrafine Particles* HPHCs Tumor progression & Invasiveness*** * Balkwill F and Mantovani A. Inflammation and cancer: back to Virchow? Lancet, 2001, 357: ** You et al. Nanoparticulate carbon black in cigarette smoke induces DNA cleavage and Th17-mediated emphysema. elife 2015; 4:e09623 *** Rothwell et al. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 2011; 377:

42 Lung Cancer Study - Design 26.8 µg/l nicotine concentration in IQOS aerosol represents 56 Sticks/day* Study Groups Nicotine in test atmosphere Female A/J mice Male A/J mice Air 0 µg/l n = 75 n = 118 3R4F 13.4 µg/l n = 75 IQOS Low 6.7 µg/l n = 74 IQOS Medium 13.4 µg/l n = 75 IQOS High 26.8 µg/l n = 72 n = 97 month Interim dissections Terminal dissection Terminal dissection n = Number of animals at months 18 assessable for carcinoma incidence µg/l nicotine concentration in IQOS aerosol represents 56 Sticks/day* *FDA, Estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. Food and Drug Administration, Washington, DC. Stinn et al., 2013, Toxicology. 2013, 305: doi: /j.tox

43 I n c i d e n c e o f L u n g C a r c i n o m a ( %, M e a n S E M ) M u l t i p l i c i t y o f L u n g C a r c i n o m a ( M e a n S E M ) Incidence and Multiplicity of Lung Carcinoma Incidence Bronchiolo-Alveolar Carcinoma Multiplicity Bronchiolo-Alveolar Carcinoma d i f f. S h a m * p < * d i f f. S h a m * p < * d i f f. 3 R 4 F # p < d i f f. 3 R 4 F # p < A i r 3 R 4 F I Q O S I Q O S I Q O S A i r 3 R 4 F I Q O S I Q O S I Q O S L o w M e d H i g h L o w M e d H i g h Incidence and multiplicity of Lung Carcinomas are significantly increased upon exposure to 3R4F smoke compared to air exposure. Source: PMI Study Report of Study - Study number

44 I n c i d e n c e o f L u n g C a r c i n o m a ( %, M e a n S E M ) Incidence and Multiplicity of Lung Carcinoma Incidence Bronchiolo-Alveolar Carcinoma * # d i f f. S h a m * p < d i f f. 3 R 4 F # p < M u l t i p l i c i t y o f L u n g C a r c i n o m a ( M e a n S E M ) Multiplicity Bronchiolo-Alveolar Carcinoma * # d i f f. S h a m * p < d i f f. 3 R # p < # 4 F A i r 3 R 4 F I Q O S I Q O S I Q O S A i r 3 R 4 F I Q O S I Q O S I Q O S L o w M e d H i g h L o w M e d H i g h Incidence and multiplicity of Lung Carcinomas in IQOS exposed mice was significantly lower compared to 3R4F smoke exposed mice and similar to air exposed mice. Source: PMI Study Report of Study - Study number

45 Conclusions IQOS reduces genetic damage compared to continued smoking IQOS reduces inflammation compared to continued smoking IQOS reduces incidence and multiplicity of lung adenomas and lung carcinomas in a validated cancer animal model 45

46 Risk Assessment Model Toxic Cigarette Emissions Exposure Molecular changes Disruption of biological Mechanisms Cell/Tissue Changes Disease Population Harm Reduced Emissions Reduced Exposure Reduced Adverse Health Effects PMI Reduced Emissions of Exposure Reduction Harmful Chemicals in IQOS users Carcinomas in 18 Non-Clinical Studies and 10 Clinical Studies No solid ultrafine particles (PM 2.5) Effect on By- Standers Incidence of Lung animal model significantly reduced 46

47 What We Know Today IQOS is not risk free and is addictive and the best choice is to quit Smokers carry a time-dependent relative risk of disease based on their smoking history when they quit or switch to IQOS IQOS is a much better choice for smokers than to continue smoking cigarettes We all share the responsibility to provide accurate information based on sound science Consumers have the right to receive accurate and non-misleading information to make an informed, better choice for their health 47

48 This Scientific Update is issued for the purpose of publishing and disseminating scientific information and not for advertising or marketing purposes regarding tobacco or nicotine-containing products. The content of this Scientific Update is not and should not be regarded as an offer to sell, or a solicitation of an offer to buy, any product of PMI or its affiliates. The content on this Scientific Update is also not and should not be regarded as a promise, warranty, characterization or guarantee regarding any product of PMI or its affiliates. 48