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Cynthia F. Caracta, MD, FCCP Assistant Professor of Medicine

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Presentation on theme: "Cynthia F. Caracta, MD, FCCP Assistant Professor of Medicine"— Presentation transcript:

1 Sex differences in lung cancer and tobacco-related lung disease: health concerns for women vs. men
Cynthia F. Caracta, MD, FCCP Assistant Professor of Medicine Division of Pulmonary, Critical Care, and Sleep Medicine

2 Sex Differences in Lung Cancer
Epidemiology of lung cancer in women Epidemiology of smoking and COPD in women Changes in histology of lung cancer in women vs. men Factors attributed to the pathogenesis of female lung cancer: environmental, behavioral, genetic/molecular epidemiology, and gender/hormonal Clinical responses to therapy and survival in lung cancer Targeting of women and young adults by the tobacco industry Prevention of lung cancer and COPD Effects of smoking on other cancers Outline of talk: Epidemiologic and experimental evidence suggest that gender may play a role in the incidence and progression of lung cancer. In this talk, I will try to outline the current evidence and possible explanations for this observation.

3 Lung Cancer Epidemiology
Worldwide most frequent cancer: 12% of all newly diagnosed cancers US 25% of all cancer-related deaths: SEER 2003 predictions 212,600 new cases (women and men) and 157,200 new deaths (68,800 women and 88,400 men) For 2005 estimated 172,570 new cases (79,560 women and 93,010 men) and 163,510 deaths (73,020 women and 90, 490 men) 90% tobacco-related/ 10% nonsmokers (2-3% passive smoke) 30% adult Americans smoke/ 70% ages 9-12 have tried cigarettes Gender , Race, and geographic disparities suggest cancer risk depends on exposure and individual susceptibility Worldwide lung cancer is the most frequent cancer and is the most frequent cause of cancer-related deathe in both men and women in the US surgeon general implicated tobacco smoke in lung cancer. There is a 20 fold greater cancer risk in smokers vs. neversmokers. ETS is responsible for approx 3000 cancer deaths per year. Ref CA Cancer J Clinics 2005, Jemal et al. NSCLCs 75% pf primary lung cancers Small cells: 20% Remaining 5% carcinoids, sarcomas, and unclassified neoplasms 90% of all lung cancers are directly attributable to tobacco and may influence the incidence and histology; however only 10% of smokers go on to lung cancer while 10% of those who get lung cancer are non-smokers-what are the mechanisms in these populations and are there differences in their pathogenesis???? RR of lung cancer ranges between 10 and 20 in smokers vs nonsmokers. Following smoking cessation, RR remains at 15 for 5 years, decreases to 7 from 5-9years, and plateaus between 2-5 thereafter so that RR never returns to baseline so that 50% of lung cancer occur in former smokers. 30% of adult Americancs smoke, while the increase in teenage smoking continues to provide the next generation with new lung cancer candidates: 70% of children between ages 9-12 admit to having tried cigarette smoking more than 3,000 under age 18 try smoking qd- >1 million q Year roughly 20-30% highschool teens smoke regularly Gender differences: suggest that the RR for lung cancer in women given the same smoking exposure is 1.5 to X that of men. Race differences: For men, lung cancer ranks as second highest cancer site after prostate cancer at a rate of 73/100k. However, the rates vary widely from low of 38/100k in Hispanics to 111/100k for blacks. For women: second highest cancer for white and black but third for hispanics ranging from 19/100k for hispanics to 45.8/100k in blacks and whites. Lung cancer incidence among whites =blacks < Hispanic=AI/AN=API based on SEER data These higher incidence rates in blacks and lower survival rates vs whites have been attributed to smoking habits, socioeconomics, genetic susceptibility, occupational exposure, diet and differences in treatment/surgical rates. Overall the five-yr survival rate is 14% whites/11%blacks. Black men higher smoking rates 34 vs 28% while black women have lower rates than whites.22 vs 25% may partially explain incidence rates. Lung ca rates AA females= white females;Aamales 50% more than whites; Mortality <<Hiispanics,Native Americans, Asian Pacific Islanders as compared to AA and nonhispanic whites; Urban areas vs rural and developed vs. underdeveloped having greater rates of lung ca Higher death rates may be due to : health-related behavior, eg mentholated/higher tar and nicotine cigarettes; blacks have higher blood levels of cotinine (main nicotine metabolite) and may excrete or metabolize differently; Have different medical/surgical access; ?racial barrier .

4 Female Death Rates From Lung Cancer — A Global Perspective
United Kingdom 20.9 Denmark 24.9 Canada 22.9 New Zealand 17.6 • The United States has the highest female lung cancer death rate in the world. • The tobacco epidemic is pandemic — it spans the globe. Now that the marketplace for cigarettes in the United States is changing (albeit slowly) due to new legislation and healthcare advocacy efforts, tobacco companies are increasingly looking for previously untapped markets, and profits, abroad. • In 1970, the World Health Organization (WHO) took a public position against smoking. • In 1990, WHO issued “Guidelines for Controlling and Monitoring the Tobacco Epidemic” to assist countries in developing national action plans, enacting the plans, and collaborating with governments, organizations, and businesses. • Increasingly, countries are working together to address the tobacco issue. For example, in 1996, the United States-Mexico Binational Commission met to coordinate activities and exchange ideas for four high priority areas of health, including tobacco use prevention. United States 26.3 , Age Adjusted Per 100,000 American Cancer Society, Cancer Facts and Figures, 1998

5 Global lung cancer mortality
Didowska, et all BMJ 2005: Lung cancer mortality at ages in the EU: ecological study of evolving tobacco epidemics Mortality from lung cancer in women is still rising in most EU countries, except for the UK and to some extent, Ireland and Denmark. The greatest increases in the past decade were in France, Spain, and Hungary with estimated annual % changes of 7.2, 6.8, and 6%, respectively. Lung cancer mortality in male populations of central and eastern Europe since the mid 1990’s imply that trends in tobacco exposure in young men have been favourable since the early 1980’s. Lung cancer epidemics among women show no consistent pattern that follows those in men either in timing or in relative magnitude. Lung cancer mortality at ages in the EU: ecological study of evolving tobacco epidemics: BMJ 331:july 2005, Didkowska see figure.

6 France  7.2% Hungary  6.0% Spain  6.8%  UK
Lung cancer mortality in the European Union at age Dotted (blue) lines denote standardised mortality for lung cancer; solid (red) lines denote time trends calculated by software Joinpoint (http://srab.cancer.gov/joinpoint). Cyprus was not included in the analysis because of lack of data. Didkowska, J. et al. BMJ 2005;331: France  7.2% Hungary  6.0% Spain  6.8%  UK Copyright ©2005 BMJ Publishing Group Ltd.

7 Global lung cancer mortality
Levi, F, et al. E J Cancer Prev 2006: Switzerland, WHO database fall in male lung cancer mortality over 20% over last decade from 42.9 to 34.3/100,000 and have leveled off to reflect recent increase in alcohol and tobacco use Increase in mortality in women by 38% between 1981 and 1991 and 47% between 1991 and 2001 to reach 10.7/100,000 and 18.3 at age 35-64 Increase in women attributed to increased prevalence of smoking Lung cancer mortality at ages in the EU: ecological study of evolving tobacco epidemics: BMJ 331:july 2005, Didkowska see figure.

8 Cancer Mortality in the United States: SEER data
Worldwide most frequent cancer: 12% of all newly diagnosed cancers US 25% of all cancer-related deaths: SEER 2003 predictions 212,600 new cases (women and men) and 157,200 new deaths (68,800 women and 88,400 men) For 2005 estimated 172,570 new cases (79,560 women and 93,010 men) and 163,510 deaths (73,020 women and 90, 490 men) 90% tobacco-related/ 10% nonsmokers (2-3% passive smoke) 30% adult Americans smoke/ 70% ages 9-12 have tried cigarettes Gender , Race, and geographic disparities suggest cancer risk depends on exposure and individual susceptibility Worldwide lung cancer is the most frequent cancer and is the most frequent cause of cancer-related deathe in both men and women in the US surgeon general implicated tobacco smoke in lung cancer. There is a 20 fold greater cancer risk in smokers vs. neversmokers. ETS is responsible for approx 3000 cancer deaths per year. Ref CA Cancer J Clinics 2005, Jemal et al. NSCLCs 75% pf primary lung cancers Small cells: 20% Remaining 5% carcinoids, sarcomas, and unclassified neoplasms 90% of all lung cancers are directly attributable to tobacco and may influence the incidence and histology; however only 10% of smokers go on to lung cancer while 10% of those who get lung cancer are non-smokers-what are the mechanisms in these populations and are there differences in their pathogenesis???? RR of lung cancer ranges between 10 and 20 in smokers vs nonsmokers. Following smoking cessation, RR remains at 15 for 5 years, decreases to 7 from 5-9years, and plateaus between 2-5 thereafter so that RR never returns to baseline so that 50% of lung cancer occur in former smokers. 30% of adult Americancs smoke, while the increase in teenage smoking continues to provide the next generation with new lung cancer candidates: 70% of children between ages 9-12 admit to having tried cigarette smoking more than 3,000 under age 18 try smoking qd- >1 million q Year roughly 20-30% highschool teens smoke regularly Gender differences: suggest that the RR for lung cancer in women given the same smoking exposure is 1.5 to X that of men. Race differences: For men, lung cancer ranks as second highest cancer site after prostate cancer at a rate of 73/100k. However, the rates vary widely from low of 38/100k in Hispanics to 111/100k for blacks. For women: second highest cancer for white and black but third for hispanics ranging from 19/100k for hispanics to 45.8/100k in blacks and whites. Lung cancer incidence among whites =blacks < Hispanic=AI/AN=API based on SEER data These higher incidence rates in blacks and lower survival rates vs whites have been attributed to smoking habits, socioeconomics, genetic susceptibility, occupational exposure, diet and differences in treatment/surgical rates. Overall the five-yr survival rate is 14% whites/11%blacks. Black men higher smoking rates 34 vs 28% while black women have lower rates than whites.22 vs 25% may partially explain incidence rates. Lung ca rates AA females= white females;Aamales 50% more than whites; Mortality <<Hiispanics,Native Americans, Asian Pacific Islanders as compared to AA and nonhispanic whites; Urban areas vs rural and developed vs. underdeveloped having greater rates of lung ca Higher death rates may be due to : health-related behavior, eg mentholated/higher tar and nicotine cigarettes; blacks have higher blood levels of cotinine (main nicotine metabolite) and may excrete or metabolize differently; Have different medical/surgical access; ?racial barrier .

9 Estimated New cases and Estimated New Deaths
from Selected Cancers for 2005 in the US While breast and prostate remain the number one newly diagnosed cancers, cancer of the lung and bronchus cause more deaths than any other cancer. From Jemal, A. et al. CA Cancer J Clin 2005;55:10-30. Copyright ©2005 American Cancer Society

10 Annual Age-adjusted Cancer Incidence Rates among Males and Females for Selected Cancer Types, US, 1975 to 2001 What are some of the reasons for this rise in cancer and when do we expect it to plateau? From Jemal, A. et al. CA Cancer J Clin 2005;55:10-30. Copyright ©2005 American Cancer Society

11 Annual Age-adjusted Cancer Death Rates Among Females for Selected Cancer Types
US, 1930 to 2001 Not only as incidence rises, the death rate due to lung cancer has risen. From Jemal, A. et al. CA Cancer J Clin 2005;55:10-30. Copyright ©2005 American Cancer Society

12 Smoking in the US and lung cancer
Worldwide most frequent cancer: 12% of all newly diagnosed cancers US 25% of all cancer-related deaths: SEER 2003 predictions 212,600 new cases (women and men) and 157,200 new deaths (68,800 women and 88,400 men) For 2005 estimated 172,570 new cases (79,560 women and 93,010 men) and 163,510 deaths (73,020 women and 90, 490 men) 90% tobacco-related/ 10% nonsmokers (2-3% passive smoke) 30% adult Americans smoke/ 70% ages 9-12 have tried cigarettes Gender , Race, and geographic disparities suggest cancer risk depends on exposure and individual susceptibility Worldwide lung cancer is the most frequent cancer and is the most frequent cause of cancer-related deathe in both men and women in the US surgeon general implicated tobacco smoke in lung cancer. There is a 20 fold greater cancer risk in smokers vs. neversmokers. ETS is responsible for approx 3000 cancer deaths per year. Ref CA Cancer J Clinics 2005, Jemal et al. NSCLCs 75% pf primary lung cancers Small cells: 20% Remaining 5% carcinoids, sarcomas, and unclassified neoplasms 90% of all lung cancers are directly attributable to tobacco and may influence the incidence and histology; however only 10% of smokers go on to lung cancer while 10% of those who get lung cancer are non-smokers-what are the mechanisms in these populations and are there differences in their pathogenesis???? RR of lung cancer ranges between 10 and 20 in smokers vs nonsmokers. Following smoking cessation, RR remains at 15 for 5 years, decreases to 7 from 5-9years, and plateaus between 2-5 thereafter so that RR never returns to baseline so that 50% of lung cancer occur in former smokers. 30% of adult Americancs smoke, while the increase in teenage smoking continues to provide the next generation with new lung cancer candidates: 70% of children between ages 9-12 admit to having tried cigarette smoking more than 3,000 under age 18 try smoking qd- >1 million q Year roughly 20-30% highschool teens smoke regularly Gender differences: suggest that the RR for lung cancer in women given the same smoking exposure is 1.5 to X that of men. Race differences: For men, lung cancer ranks as second highest cancer site after prostate cancer at a rate of 73/100k. However, the rates vary widely from low of 38/100k in Hispanics to 111/100k for blacks. For women: second highest cancer for white and black but third for hispanics ranging from 19/100k for hispanics to 45.8/100k in blacks and whites. Lung cancer incidence among whites =blacks < Hispanic=AI/AN=API based on SEER data These higher incidence rates in blacks and lower survival rates vs whites have been attributed to smoking habits, socioeconomics, genetic susceptibility, occupational exposure, diet and differences in treatment/surgical rates. Overall the five-yr survival rate is 14% whites/11%blacks. Black men higher smoking rates 34 vs 28% while black women have lower rates than whites.22 vs 25% may partially explain incidence rates. Lung ca rates AA females= white females;Aamales 50% more than whites; Mortality <<Hiispanics,Native Americans, Asian Pacific Islanders as compared to AA and nonhispanic whites; Urban areas vs rural and developed vs. underdeveloped having greater rates of lung ca Higher death rates may be due to : health-related behavior, eg mentholated/higher tar and nicotine cigarettes; blacks have higher blood levels of cotinine (main nicotine metabolite) and may excrete or metabolize differently; Have different medical/surgical access; ?racial barrier .

13 Cigarette Use Among High School Students — 1998
By Gender By Grade Level 34.7% 37.7% 36.4% 33.4% 35.3% 36.6% 39.6% 9th Grade 10th Grade 11th Grade 12th Grade Females Males Total • After years of remaining steady, the rates in teenage smoking increased each year since 1992, with 36.4% of high school students were current tobacco users in There was a drop in 1998, with 34.8% reporting current tobacco use.2 • Both sexes are now equally likely to smoke cigarettes in high school.1 In 1999, 28.7% of high school boys and 28.2% of high school girls reported they currently smoke cigarettes.2 • Young people are a strategically important market for the tobacco industry. Since most smokers try their first cigarette before the age of 18, young people are the chief source of new consumers for the tobacco industry, which each year must replace the many consumers who quit smoking or die from smoking-related illnesses. • Teenage girls often start to smoke to avoid gaining weight. Social images can convince teens that being slightly overweight is worse than smoking. The tobacco industry cashes in on and often creates these social images. • Smoking is often a self-enhancement mechanism for teens who have lower self-esteem and self-images than have their nonsmoking peers. • Adolescents with lower levels of school achievement are more likely than their peers to use tobacco. • Adolescents have ready access to cigarettes, despite federal regulations governing their sales to minors. According to the FDA, children were able to buy tobacco products 25% of the times they tried, with that rate being much higher in some states.3 Males Total MMWR. 1998;47(SS-3):50. 1 University of Michigan’s Monitoring the Future Study, 1998. 2 MMWR. 1998;47(SS-3):50. 3 Food and Drug Administration, 1999

14 Smoking prevalence in US by state
Shopland, et al JNCI 1996, examined smoking prevalence in 50 states and District of Columbia from census survey data collected in 1992 and 1993 from 266,988 adults smokers included anyone who had smoked 100 cigarettes and was currently smoking every day or just on some days Substantial geographic variation: 17.1% Utah; 19.5% California 20.7% New Jersey, 22% New York, Nebraska, and Hawaii 30% Kentucky and West Virginia

15 Smoking prevalence in the US by state
Balluz, et al MMWR, 2004, examined data from 2003 among selected local areas in the US via cross-sectional random phone survey (BRFSS) Looking at statewide including Guam, Puerto Rico and Virgin Islands: the estimated prevalence of persons who reported ever smoking ≥100 cigarettes and who currently smoke was 19% in New Jersey and 22.3% in New York (see table 11) Alaska 30%; Kentucky 30%; Utah 12.8% BRFSS is the Behavioral risk Factor Surveillance System survey conducted by the state health departments as a source for information on healht-risk behavior, preventive health practices, and access to health care since 1984.

16 US smoking prevalence in 2002 by state
Alaska 29.3% Kentucky 32.6% N.Y. 22.3% Utah 12.8%

17 Lung cancer and sex Sex differences in Lung Cancer
Changing histology and role of cigarette type/practices Role of the tobacco industry in promoting tobacco use Factors attributed to the pathogenesis of female lung cancer: environmental, behavioral, genetic/molecular epidemiology, and gender/hormonal Molecular variables Polymorphisms/metabolism of tobacco-related carcinogens (sex-related susceptibility) Molecular abnormalities (increased kras or GFRs (GRPR, ERBB2); decreased DRC Hormonal (estrogens) Risk may be greater in women???? Better outcome stage for stage? Better response to cis-platin based tx? Increase in COPD incidence/mortality?

18 Changes in lung cancer histology
1980’s adenocarcinoma surpassed squamous cell: US, Italy, Nordic countries and Japan SEER data RR women :1.5 8.1 and in men 4.6  19.0 for adenocarcinoma Role of filtered cigarette in the change in histology from central squamous to peripheral adenocarcinomas of the lung MD Anderson study SEER data cocumented that patiens age <50 presented with more advanced disease. They tried to determine wheter differences in survival exist between <50 and >50 year old patients with adenocarcinoma matched for stage, gender, and definitive therapy modality. There were no significant differences with regard to overall survival or time to progression nor was smoking status predictive for survival. However, a surprisingly higher percentage of the younger patients were FEMALE (45%) and NEVERSMOKED (26% suggesting that other factors may be involved in pathology of adeno (in females). Sekine Jpn J Can Res 1999: retrospectively studied the effect of smoking on tumor progression in 3312 registered lung cancer patients between 1977 and women 38.9% smokers and 73.6% had adenoca vs 2369 men 95% were smokers and 42.% had adenoca. They found the odds ratios for advanced disease and the hazard ratio for survival to be increaed in women with adenocarcinoma and closely correlated with smoking history. This association was not observed in women with non-adenocarcinoma and weaker in men suggesting various effects on smoking on lung cancer development depending on gender and histological type of tumor. This leads us to factors involved in the pathogenesis of Women’s lung cancer.

19 Cancer Incidence Rates, US 1973-1996
Overall Incidence Incidence: Histology Rates per 100,000, age-adjusted Source: SEER

20 Figure 1. Age-standardized female lung cancer incidence rates for all lung cancers and for two of the four major histologic types (SEER areas, ) Jemal, A. et al. Cancer Epidemiol Biomarkers Prev 2005;14: Copyright ©2005 American Association for Cancer Research

21 Lung cancer and sex Sex differences in Lung Cancer
Changing histology and role of cigarette type/practices Role of the tobacco industry in promoting tobacco use Factors attributed to the pathogenesis of female lung cancer: environmental, behavioral, genetic/molecular epidemiology, and gender/hormonal Molecular variables Polymorphisms/metabolism of tobacco-related carcinogens (sex-related susceptibility) Molecular abnormalities (increased kras or GFRs (GRPR, ERBB2); decreased DRC Hormonal (estrogens) Risk may be greater in women???? Better outcome stage for stage? Better response to cis-platin based tx? Increase in COPD incidence/mortality?

22 Role of tobacco companies in promoting smoking:
* Tobacco companies use niche marketing to target those groups of women most likely to smoke. * Currently, 80% of marketing budget spent on promotions, 20% on advertising. * Thirty-five percent (7.4 million) 12 to 17 year olds have responded to tobacco promotional programs. • Increasingly, tobacco companies use niche marketing to target those groups of girls and women most likely to smoke. They are also preparing for potential marketing restrictions by compiling extensive mailing lists for direct-to-consumer marketing. • In 1994, the tobacco industry spent $850 million, or >17% of their annual advertising expenditures, on distributing specialty items. Currently, 80% of their marketing budget is spent on promotions, and 20% on advertising. • Thirty-five percent (7.4 million) 12 to 17 year olds have responded to tobacco companies’ promotional campaigns. Slide A31

23 to maintain relevance with the younger market.
The left image of the stern and solitary cowboy is a Marlboro advertisement from 1960; the right image, updated to show friendly cowboys socialising, is from 1999. As the values of young people in the USA shifted away from rugged individualism and toward a sense of community, PM attempted to update the Marlboro Man image to maintain relevance with the younger market. The Marlboro Man in the 1990s began to smile, socialise, enjoy leisure time, and show his softer, more accessible side. Anderson, S J et al. Tob Control 2005;14: Copyright ©2005 BMJ Publishing Group Ltd.

24 Figure 1 In this 1983 Satin "Couch" advertisement, the caption reads, "Go ahead. You deserve this Satin moment. So enjoy the smooth, silky taste of new Satin with the luxurious Satin tip". With the Satin brand and advertising campaigns, Lorillard attempted to capture a sensuous image of highly feminine--not feminist--women. This campaign was designed to communicate a self indulgent, relaxing, escapist fantasy for mature, busy women, whether employed or not, who felt pressured by many demands on their time. Anderson, S J et al. Tob Control 2005;14: Copyright ©2005 BMJ Publishing Group Ltd.

25 Figure 2 With the 1986 Benson Hedges "For People Who Like to Smoke" campaign "Living Room Girls" execution, PM attempted to combat the declining social acceptability of smoking through brand image. "For People Who Like to Smoke" depicted casual, jovial scenes of upper middle class people enjoying meaningful time with friends and family, where conflict between smokers and non-smokers was entirely absent. Anderson, S J et al. Tob Control 2005;14: Copyright ©2005 BMJ Publishing Group Ltd.

26 Figure 3 The left image from the 1997 Capri "She's Gone to Capri" campaign includes a model; the right image from 1999 excludes the model from the same scene. Like Satin, Capri targeted highly feminine women who felt a need for a luxurious escape from life's stresses. Brown Williamson found that excluding models from the ads and using impressionistic print techniques enhanced the dreamy, escapist feel of the image and created a more personal place to which the target audience could escape. Anderson, S J et al. Tob Control 2005;14: Copyright ©2005 BMJ Publishing Group Ltd.

27 Figure 5 The left image is from the Virginia Slims "You've Come a Long Way, Baby" campaign in 1978; the right is from the "It's a Woman Thing" campaign in Virginia Slims' core user group was aging, and by the mid 1990s the feminist appeal of the long running "You've Come a Long Way, Baby" campaign was not well received by many younger women. PM recreated the Virginia Slims image by downplaying feminism and emphasising gender stereotyped female relationships. The caption of the right image reads, "If our best friend seems to know everything about us it's because she does. Virginia Slims. It's a woman thing". Anderson, S J et al. Tob Control 2005;14: Copyright ©2005 BMJ Publishing Group Ltd.

28 Lung cancer and sex Sex differences in Lung Cancer
Changing histology and role of cigarette type/practices Role of the tobacco industry in promoting tobacco use Factors attributed to the pathogenesis of female lung cancer: environmental, behavioral, genetic/molecular epidemiology, and gender/hormonal Molecular variables Polymorphisms/metabolism of tobacco-related carcinogens (sex-related susceptibility) Molecular abnormalities (increased kras or GFRs (GRPR, ERBB2); decreased DRC Hormonal (estrogens) Risk may be greater in women???? Better outcome stage for stage? Better response to cis-platin based tx? Increase in COPD incidence/mortality?

29 The Scheme: From Exposure to Lung Cancer
Cigarette smoking Metabolic Activation eg. Cytochrome P450 Persistence Proliferation Metabolic Detoxification eg. Glutathione S-Transferase, Repair To understand the importance of molecular alterations and the selection of targets, it is necessary to quickly review the numerous steps that occur over 30 years, resulting in lung cancer in a small group of susceptible individuals. Key: lung cancer represents the interaction between exposure to environmental mutagens and genetic susceptibility. Carcinogens and carcinogen metabolism exemplified by cigarette smoke: tobacco smoke produces electrophilic metabolic intermediates of polycyclic aromatic hydrocarbons (PAHs) Multiple forms of cytochrome p450 enzymes activate these compounds and lead to DNA sdduct formng intermediates (epoxides) that are detoxified futher by additional steps in metabilism. This model of carcinogen metabolism suggests that the precise balance betweeen activation of procarcinogens and detoxification of reactive intermediates is critical to the estimation of individual risk of cancer from environmental exposures. In addition to PAHs, N-nitroso compunds in tobacco smoke are potent lung carcinogens. Acommon end result of carcinogen damage is mediated through the oxidative processs and the development of reactive metabolic intermediates that bind to DNA covalenly and are usually targeted for repair. Genetically heritable DNA repair defects are clearly associated with cancer development. If they persist, mutations result that can lead to the activation of an oncogene or deactivation of a tumor suppressor gene. Liu, et al 2005. Apoptosis Excretion Normal DNA Modified from Hecht JNCI; 1999

30 Polymorphisms and lung cancer in women: Glutathione-S-transferase M1 polymorphism
GSTM1 -inherited deletion is thought to be a cancer susceptibility marker catalyzes the metabolic detoxification of PAH’s, styrene, and ethylene oxides in cigarette smoke; gene is absent in 40-50% US population; homozygous deletion leads to increased SCE, PAH adducts, and mutagenicity. OR for lung cancer increased in smoking women 3 vs.1.4 men (Tang Carcinogenesis 1998) and in ETS GSTM1 null vs. non –null at 2.6 (Bennett JNCI 1991. These types of differences suggest that sex may play a role in ability to detoxify environmental carcinogens and increase risk of lung cancer in women… How is this relevant to gender?

31 DNA adducts and damage in women’s lung cancer
PAH-DNA adducts shown to be increased in females for all levels of smoking compared to men Ryberg Cancer Research 1994 Tang Can Epi Biomarker Prevention 1995 Mollerup Cancer Research 1999 Ryberg and Mollerup two Norway studies: Ryberg examined normal lung tissues in 63 previously untreated lung cancers and Mollerup extended to 159 cases with similar results. Tang found increased DNA adducts in blood leukocytes were higher in cases than in controls and adducts increased with the no of cigarettes among the current smokers with lung cancer DNA adducts correlate with cancer risk suggestive that women may be more susceptible to DNA damage by tobacco smoke leading to increased risk for lung cancer than men… modified fromCAPowell 10/2000

32 Genes in lung cancer in women: K-ras & p53
K-ras proto-oncogene --most mutations reported in smokers 30% from adenocarcinoma’s % in codon GT transversion --Wang J Can Res Clin Onc 1998: no K-ras mutation in population of nonsmoking women with adenocarcinoma; -- Nelson JNCI 1999: K-ras mutation marker of aggressive adenocarcinoma in smoking women; These findings suggest that the mechanisms for lung cancer may be different in smoking and nonsmoking women… Wang patients with resected Stage 1 adenocarcinomas were studied for K-ras gene mutations. 5/84 (6%) had mutations with 4/5 occurring in exon 1 in codon 12 or 13. All mutations occurred in males who were smokers. Note that Taiwanese women are predominantly nonsmoking vs males. Nelson, examined role of sex in ssmoking and survival. Studied K-ras mutation in codon 12, as a specific marker found in adenocarcinoma’s in women Mass Gen. K-ras was associated only in smokers and was more likely to be found in women than men with an or of 3.3 ( ) Decreased survival was noted only for stage I tumors.

33 K-ras and p53 in women’s lung cancer
P53 tumor supressor gene mutations occur in regions between exons 4 and 8 -- GT transversions and hotspots in lung tumors smokers --Kure Carcinogenesis 1995: increased p53 mutations in females vs. males with NSCLC --Gealy Can Epi Biomarkers and Prev 1999: frequency of K-ras mutation increased in smoking women with lung cancer, but same type of mutation as in men; p53 same frequency but different type of mutation than men. These findings suggest that women may develop lung cancer differently than men… Hotspots codons ,179, , 273 and 282 Tseng cancer Res samll cells 37 m 28f :noted decreased mutations in p53 in small cell lung cancer and none from females contained more than one mutation whereas four form the males contained more than one. Most common mutaiton was 27%AG transition, then17% GT transversion, then12% GA transition. Pathways in small cell in women may not involve p53

34 Growth Factors in lung cancer in women: GRPR and EGFR
GRPR bombesin-like peptide autocrine growth factor gene located on xp22.3-p21 Escapes inactivation in females and may be activated earlier in females in response to tobacco exposure % Individuals with GRPR mRNA in Normal airway cells (n=78) Pack-years Males Females 55 1-25 20 75* 26-49 75 70 > 50 59 69 GRP a member of the bombesin-like peptide family Autocrine growth factor for lung cancers. Mediated through family of G protein coupled bombesin receptors (GRPR, neuromedin B receptor and bombesin receptor subtypes 3. Both the GRPR other family members are expressed in NSCLC and gene transfer confers increased growth response to GRP in cultured immortalized bronchial epithelial cells. GRP and GRPR message increased in smokers compared to non smokers. (urine for GRP) Shriver at U Pittsburgh et al studied GRPR mRNA in lung tissue and cultured cells from 40 males and 38 females. They showed increased expression of the receptor in females compared to males, for all levels of smoking history. The authors suggested that the presence of two expressed copies of the gene may be a factor in women increased susceptibility to lung cancer. mRNA expression in female nonsmokers and short term smokers 55% vs men 0% (p=0.018) Shriver JNCI 92:24, 2000 modified from CAPowell 10/2000

35 Epidermal Growth Factor Receptor (EGFR)
EGFR family: (epidermal growth factor receptors) are transmembrane tyrosine kinases that mediate cell growth, differentiation, and survival after receptor phosphorylation EGFRs are overexpressed esp in NSCLCs and work through several pathways. ERBB family: ERBB1 and ERBB2 (epidermal growth factor receptors) are transmembrane tyrosine kinases that regulate proliferation and differentiation via intracellular signal transduction cascades (e.g. MAP kinase pathway) ERBB1 overexpressed by unknown mechanism and involves autocrine loop esp in NSCLCs producing ERBB and transforming growth factor b ERBB2 (HER2/neu) 30% of NCSLCs, esp adenoca and associated with multiple drug resistance phenotype and increased metastatic potential Clinical trials of monoclonal antibodies to ERBB1 (c225 or Cetuximab/Erbitux, Imclone Systems Inc) and ERBB1 blockers CP358774( Erlotinib) and ZD1839(Iressa) ERBB2 monoclonal abs Herceptin: combined with chemotx in lung and breast clinical trials

36 Which tumors exhibit the EGFR mutations?
Bardelli, et al Science 2003: genome wide screening approach in NSCLC tumors EGFR mutations were more frequent in adeno ca, in women, and in Japanese patients and these patients had the better clinical responses to geftinib Pao, et al, Proc Nat Acad Sci USA, 2004: similar EGFR mutations in previous studies associated with responses to erlotinib in NSCLC EGFR mutations more commonly in tumors with BAC features, in nonsmokers, females, adenocarcinomas, and patients of East Asian origin. No EGFR TK domain mutations have been found in tumors other than NSCLCs These findings suggest that sex may influence how lung cancer develops and how women may respond to targeted chemotherapeutic agents… Tumor profiling!!!! Issue of multiple mutations in same tumor….

37 Role of estrogen and estrogen receptors in women’s lung cancer
Animal studies show increased incidence of pulmonary neoplasms in animals receiving estrogen; Women receiving exogenous estrogen replacement therapy have increased risk of adenoca of lung and effect with smoking is additive vs. early menopause Taoili JNCI 1994; Differential tissue expression of ER members in animal and human tissues including lung and lung cancer cell lines Lung tumors have been shown to exhibit estrogen receptors and lung cancer cells have been shown to be stimulated upon exposure to estrogen and inhibited by antiestrogens in cell cultures Role of estrogen in lung cancer unclear but the estrogen receptor may mediate lung cancer through EGFR Rationale for studying estrogen in women’s lung cancer: Epidemiological evidence discussed Estrogen – responsive cancer models (breast, endometrium) Localization of ER to normal lung and lung tumors Different forms of ER may play different roles in pathogenesis of lung cancer and therapy.

38 Lung cancer and sex Sex differences in Lung Cancer
Changing histology and role of cigarette type/practices Role of the tobacco industry in promoting tobacco use Factors attributed to the pathogenesis of female lung cancer: environmental, behavioral, genetic/molecular epidemiology, and gender/hormonal Molecular variables Polymorphisms/metabolism of tobacco-related carcinogens (sex-related susceptibility) Molecular abnormalities (increased kras or GFRs (GRPR, ERBB2); decreased DRC Hormonal (estrogens) Risk may be greater in women???? Better outcome stage for stage? Better response to cis-platin based tx? Increase in COPD incidence/mortality?

39 Clinical studies in lung cancer presentation, diagnosis, therapy, and response to therapy
Gender differences in presentation ? Gender differences in diagnosis? Gender differences in therapies offered or received? Gender differences in survival or physiological response to medical or surgical treatment? Gender differences in psychological response to diagnosis or treatment?

40 Differences in Presentation
Overall, retrospective studies reveal differences in clinical presentation of lung cancer between men and women In clinical studies of patients undergoing major curative lung resection for NSCLC, women (Romano, 1992; Quelette, 1998;Ferguson, 1999; dePerrot, 2000; Minami, 2000; Alexiou, 2002;Radzikowska, 2002; Kutlay, 2003, Batevik, 2004,Moore, 2004, Visbal, 2004, Chen, 2005, Little, 2005,Ringer, 2005, Yang, 2005) Are younger Smoke less Majority present with adenocarcinoma Tend to present with earlier stages of lung cancer

41 Gender associated differences in presentation, therapy and prognosis of lung cancer
Ouellette Ann Thor Sx 1998 --208 cases small and NSCLC retrospective study small survival advantage in women according to stage --different presentations men: pain, hemoptysis, cough --women: pain, cough, dyspnea --no difference in stage or tx Bouchardy Cancer 1999 428 patient case control study Found age, histology, and stage influenced prognosis Women more adeno: men more squamous ca Women had 2.1 x increased long-term survival No difference in tx received Suzuki Cancer 1999 430 cases Stage I NSCLC Found no impact of gender on survival Bouchardy et al looked at lung term survival in a population-based study of determinants of long term survival after surgery for cancer of the lung: Patients from the Geneva Cancer Registry between 1977 and 1987. 428 patients/98 alive at 10 years after initial diagnosis 330 controls chance of long term survival for women vs men after considering gender, age at diagnosis, place of birth, period of diagnosis, origin of dx (screening vs. other); symptoms present at dx, stage at dx, histology, and differentiation.

42 Gender associated differences in presentation, therapy and prognosis of lung cancer
Ferguson Ann Thor Sx 2000 De Perrot J Thor and CVSx 2000 Retrospective study 839 men and 198 women Women more asymptomatic, non/light smokers Women more adeno(54%) vs squamous(65% in men Survival advantage in women (hazard ratio of 0.72) DePerrot retrospective study of NSCLC females were significantly more asymptomatic (32 vs. 20% p=0.006) nonsmokers, (27 vs 2% p<0.001); light smokers (31py vw 52 py p<0.001) 65% men had squamous, and 54% women had adeno. Pre-op FOB 49% vs. 69% in men p<0.001, women got more pre-op FNAs, and fewer pneumonectomies (22 vs 32% p<0.01) Survival multivariate analysis showed females had better survival (0.72 (( CI95%) p<0.009. Ferguson showed association/trend toward better survival in women over men partially due to adenoca more commen in women vs squamous in men. No differences in therapy or treatment received or operative mortality. Women younger, more asymptomatic, non/light smokers, more adeno, stage I presentation. Small survival advantage

43 Ferguson, MK, et al, Ann Thoracic Surg 2000;69:245-50
Looking at “sex associated differences in presentation and survival of pts undergoing major lung resection for cancer: Ferguson et al looked retrospectively at 451 patients stages I through IV: All patients received intraoperative F OB/ cervical or parasternal med with CT abnormal nodes or ???T3dz. Women were younger, smoked less, slightly higher Stage I distribution, and similar distribution of resection extent and operative mortality as compared to men.

44 Ferguson, MK, et al, Ann Thoracic Surg 2000;69:245-50
Looking at all stages: women tended to have a small survival advantage. But looking at stage I women had a significantly better median survival than men. Ferguson, MK, et al, Ann Thoracic Surg 2000;69:245-50

45 Alexiou, C, et al. European J of Cardiothoracic Sx 2002; 21:319-325
Alexiou, et al prospectively looked at 833 patients 581 males vs 252 females undergoing resection for NSCLC. Patients differed at presentation: women significantly younger (62.6+/-7.8 vs 64.7=/-6.9 years p=0.006);and women had significantly less CAD, BMI, DM, pneumonectomies, and more non-smokers. Not all got meds. Prospective study 833 patients: 581 males vs. 252 females undergoing resection for NSCLC. Patients differed at presentation: women significantly younger, had significantly less CAD, BMI, DM, pneumonectomies, and more were non-smokers.

46 Alexiou, C, et al. European J of Cardiothoracic Sx 2002; 21:319-325
Operative Mortality by gender according to procedure: Alexiou, et al prospectively looked at 833 patients 581 males vs 252 females undergoing resection for NSCLC. Patients differed at presentation: women significantly younger (62.6+/-7.8 vs 64.7=/-6.9 years p=0.006);and women had significantly less CAD, BMI, DM, pneumonectomies, and more non-smokers. Not all got meds. Cox proportional hazards model revealed that pathological stage (p=0.0001), female gender (p=0.0006), and squamous cell type (p =0.001) were independent predictors of survival.

47 female p=0.006 male male Adapted from Alexiou, C, et al. European J of Cardiothoracic Sx 2002; 21:

48 female p=0.01 male Adapted from Alexiou, C, et al. European J of Cardiothoracic Sx 2002; 21:

49 female p=0.002 pP male Adapted from Alexiou, C, et al. European J of Cardiothoracic Sx 2002; 21:

50 Radzikowska, et al, Annals of Oncology 2002;131087-1093
20, 561 patients 17,686 males 2875 females Women were younger smoked less, exhibited more adenoca, and differed in stages. Community-based cancer registry of the Pulmonary outpatient departments on 20,561 pateints diagnosed in Poland from 1995 to women and men

51 Adapted from Radzikowska, et al, Annals of Oncology 2002;131087-1093
Absolute survival shows women have a significant advantage over men. Adapted from Radzikowska, et al, Annals of Oncology 2002;

52 Gender and early mortality after lung resection in the elderly
Rostad, 2005: Eur J Cardiothorac Surg;27:325-8 Norway from 1993 to 2000 all elderly patients resected for lung cancer found higher morality rate after pneumonectomy and in men undergoing bilobectomy and pneumonectomy compared to women (25 vs 7.5%) Brunelli, 2005: Eur J Cardiothorac Surg;27:325-8 Similar findings in 402 patients older than 70 operated for lung cancer from 1994 to 2004 Higher cumulative mortality rate in men compared to women (7.4 vs 0, respectively; p=0.02) This may be due to increased co-morbidities in men vs. women and due to a higher proportion of pneumonectomies in men.

53 Clinical response to lung cancer therapy
Moore, 2004 Acta Oncol.: Retrospective study of 7,553 patients with NSCLC between in USA Gender was important risk factor for survival favoring women overall Women with squamous histologies had increased risk of death vs. women with other types Suggestion of gender –dependent differences in survival including a histology-specific effect in women Visbal, 2004 Ann Thorac Surg: Prospective study of 4,618 patients with NSCLC Mayo Clinic, USA (41% women 59% men) No difference between in stage and treatment between genders Men heavier smokers Adenocarcinoma most frequent histology in both genders Male gender an independent unfavorable prognostic indicator for NSCLC survival Estimated one and five year survivals for men 51% and 15% for men vs. 60% and 19% for women Data I have presented you strongly suggests that women may have a better reponse ie survival and mortality after surgical resection for lung cancer that may be especially important in the earlier stages:

54 Clinical response to lung cancer therapy
Chen, 2005 Cancer: Retrospective review of 2,712 patients from 1991 to 1999 with NSCLC in Taiwan Analyzed for age, gender, disease stage, histology, treatment modalities and survival Male female ratio 2:1 More adenoca in females and better survival in females, especially in 50 to 69 years old age group Yang, 2005 Chest: Prospective cohort study of 5,628 primary lung cancer patients between 1997 and 2002 followed through 2003 in US 56% men; 42% women Mean age dx men 66 and women 64 years old Adenoca most common More adenoca and less squamous in women vs. men Fewer never smokers and more former smokers in men Data I have presented you strongly suggests that women may have a better reponse ie survival and mortality after surgical resection for lung cancer that may be especially important in the earlier stages:

55 Clinical response to lung cancer therapy
Ringer, 2005 Clin Lung Cancer: Retrospective cohort study midwestern US 1216 men and 997 women from 1996 to 2002 identified in hospital tumor registry with lung cancer Women were significantly more likely to have adeno. No gender differences between ages or stage at diagnosis Only patients with stage I disease showed survival differences at years 2 to 5. Data I have presented you strongly suggests that women may have a better reponse ie survival and mortality after surgical resection for lung cancer that may be especially important in the earlier stages:

56 Gender differences in response to non/surgical therapy or adjuvant therapy for NSCLC lung cancer
Differences in rate of localized and distant metastasis and response to therapy Response to chemotherapy in advanced disease Response to radiation and complications

57 Keller, et al, Lung Cancer 2002;37(3):303-9
Keller, et all lu Lung Cancer 2002;37(3):303-9 evaluated the influence of gender on survival and tumor recurrence following adjuvant therapy of completely resected stages II and IIIa NSCLC participating in the ECOG. Disease recurrence patterns were similar between the genders and did not influence survival following aduvant RT or CRT administered to patients with completely resected Stages II and IIIa NSCLC.

58 Keller, et al, Lung Cancer 2002;37(3):303-9

59 Keller, et al, Lung Cancer 2002;37(3):303-9
However, women with non-squamous histology have increased survival when compared to men.p<0.01. Keller, et al, Lung Cancer 2002;37(3):303-9

60 Post recurrent survival in NSCLC after lung resection
Ichinose, et al 1994 looked at 215 patients s/p resection for NSCLC for differences in survival according to: gender, age <or>65, stage I,II,III, histology (squamous vs. nonsquamous), type of operation (pneumonectomy vs. other), adjuvant therapy before recurrence (none, mild, vs. intensive CRT+/-XRT) Multivariate analysis revealed gender and selection of adjuvant therapy were independent +prognostic factors Suggestion biologic behavior or recurrent tumor may be influenced by gender and adjuvant tx chosen before recurrence

61 The solitary brain met in lung cancer
Prophylactic cranial irradiation (PCI) in NSCLC patients Keith, B Am J Clin Onc 2002;25:583-87 Retrospective review of 119 previously untreated NSCLC patients at London Regional Cancer Center 80 patients studied all medically or surgically unresectable Stage I to III treated with CRT/XRT +/- Sx Female gender risk of recurrence of brain mets suggesting women may benefit from PCI PCI In autopsy series, lung cancer patients had a 23% overall rate of brain mets: for adeno, large cell and sclc compared to 14% for squamous. Main tx options remain WBRT (median survival 3.7 months, SX+/WBRT(11 months), or radiosx+-WBRT(10-12 months). Keith et al, retrospective analysis of 119 patients bet with histologically confirmed Stage I-III NSCLC medically inoperable or surgically unresectable. Receiving chemoexrt and of 119, 85 had stable dz. 80 pts had complete data and female gender and LDH were predictive of brain mets. What is the explanation?>>>better survival-risk of brain mets increased?

62 Surgical treatment of NSCLC brain metastasis
Two studies regarding survival after surgical treatment for brain metastasis note either no gender difference (Saitoh,Y,et al, 1999) or better survival in women (Wronski, M, et al, 1995). In autopsy series, lung cancer patients had a 23% overall rate of brain mets: for adeno, large cell and sclc compared to 14% for squamous. Main tx options remain WBRT (median survival 3.7 months, SX+/WBRT(11 months), or radiosx+-WBRT(10-12 months).

63 Gender differences in response to therapy for advanced NSCLC lung cancer
Clinical studies for unresectable or medically inoperable NSCLC suggest women have an increased survival after treatment with chemotherapy and XRT over men. O’Connell, JP, et al, 1986 Rucksdeschel, JC, et al, 1986 Johnson, BE , et al 1988 Albain, KS, et al, 1991 Paesmans, M, et al, 1995 Clinical studies suggest that females have a survival advantage after tx for advanced NSCLC. Here are the studies that report a gender advantage in terms of survival and local recurrence. We will discuss a few of them. O’Connell, JP, et al, 1996 Ramalingam, S, et al, 1998 Jirontek, M et al, 1998 Jeremic, B et al, 2003

64 Gender differences in response to therapy for advanced NSCLC lung cancer and XRT tx
Werner-Wasik, 2000 1,999 patients treated in 9 RTOG trials with thoracic XRT between 355 received chemotx remainder no chemotx No gender survival difference Shibamoto, 2001 301 patients in prospective study of patients with Stage III NSCLC investigating influence of IFI on treatment outcome and toxicity Multivariate analysis revealed female gender, KPS, and weight change/loss significant + conrol or recurrence and survival. • Etiz, 2002 Stage I-IIIB treated with XRT - younger, high PS, female gender prolonged survival

65 Gender differences in response to therapy for advanced NSCLC lung cancer and XRT tx
Robnett, TJ, et al, 2000 reported female gender as a risk factor for severe radiation pneumonitis. Robnett looked at 148 patients retrospectively with ECOG 0-1 PS treated at UPA 1/92-6/98 and examined factors including age, gender, histology, weight loss, tumor location, radiation dose, initial radiation dose, initial radiation field size, chemtx regimen, and timing of chemts. Univariate, followed by multivariate analysis and liner regression found that pre tx PS of 1, low absolute FEV1 and females more likely to develop severe RP.

66 Combined female gender and performance status PS-1
The probability of severe radiation pneumonitis as a function of gender performance status: Combined female gender and performance status PS-1 strongly associated with severe radiation pneumonitis The odds ratio after multivariate analysis for female gender was 5.1 p=0.02, while the OR for PS-1 on KPS was 7.8 p=.01. The combination of the two was much more strongly associated with severe pneumonitis. p=0.01 p=0.01 Adapted from Robnett, TJ, et al, Int. J Rad Onc Biol Phys :89-44

67 Gender differences in response to therapy for SCLC lung cancer
Clinical studies of patients with limited and extensive SCLC treated with chemotherapy and XRT suggest females have better response rates and survival. Spiegelman, D, et al, 1989 Wolf, M et al, 1991 Albain, KS, et al, 1991 Tas, F, et al, 1999 Paesmans, M, et al, 2000 Janne, PA, et al, 2002 Christodolou, C, et al, 2002 Naughton, MJ, et al 2002 Bremnes, RM, et al, 2003 Clinical studies looking at the past 3 decades suggest better response and survival of women over men in NSCLC, particulalry in limited disease. We will discuss the largest and longest studies.

68 Emerging therapies—targeted therapies for men vs. women
A new generation of cancer therapies and such studies suggest drugs behave differently in women and men Erlotinib and gefitinib appear to work best in women with NSCLC, of Asian decent, and particularly with adenocarcinoma, and with specific EGF mutations One of the issues is that routinely in clinical trials, both the gender (fewer females) and age (less elderly) and race (less blacks) in the US are enrolled making study difficult.

69 Epidermal Growth Factor Receptor (EGFR)
EGFR family: (epidermal growth factor receptors) are transmembrane tyrosine kinases that mediate cell growth, differentiation, and survival after receptor phosphorylation EGFRs are overexpressed esp in NSCLCs and work through several pathways. ERBB2 or EFGR HER2/neu subtype in 30% of NCSLCs, esp adenoca and associated with multiple drug resistance phenotype and increased metastatic potential ERBB family: ERBB1 and ERBB2 (epidermal growth factor receptors) are transmembrane tyrosine kinases that regulate proliferation and differentiation via intracellular signal transduction cascades (e.g. MAP kinase pathway) ERBB1 overexpressed by unknown mechanism and involves autocrine loop esp in NSCLCs producing ERBB and transforming growth factor b ERBB2 (HER2/neu) 30% of NCSLCs, esp adenoca and associated with multiple drug resistance phenotype and increased metastatic potential Clinical trials of monoclonal antibodies to ERBB1 (c225 or Cetuximab/Erbitux, Imclone Systems Inc) and ERBB1 blockers CP358774( Erlotinib) and ZD1839(Iressa) ERBB2 monoclonal abs Herceptin: combined with chemotx in lung and breast clinical trials

70 From Herbst, 2004 Nature Reviews: antiEgfr therapy.

71 Emerging therapies—targeted therapies for men vs. women
2004 somatic mutations in EGFR gene associated with a favorable clinical response to gefitinib and erlotinib treatment in NSCLC patients (Paez, Science; Lynch, NEJM; Pao, Proc Natl Acad Sci USA) These mutations were most frequently detected in a subpopulation of NSCLC patients with a better clinical outcome: Women; non­smokers, Japanese origin, adeno ca especially bronchioalveolar carcinoma One of the issues is that routinely in clinical trials, both the gender (fewer females) and age (less elderly) and race (less blacks) in the US are enrolled making study difficult.

72 Fig 2. Mutations in the tyrosine kinase (TK) domain of epidermal growth factor receptor (EGFR) associated with sensitivity to gefitinib or erlotinib Gefitinib is member of the anilinoquinazoline TKI’s and produced growth inibition in a variety of solid tumor types including lung, prostate, breast, colon and ovarian cancers and was also found to enhance the antitumor activity of cytotoxic agents, radiation therapy and hormone therapies. Based on IDEAL 1 in Japan and Europe and IDEAL-2 in US it received approval in Japan and South Korea in July 2002 as second-line chemo for advanced NSCLC andin May 2003 in the US as third-line monothera;y in advanced NSCLC at 250 mg/day. Phase III INTACT-1 trial and INTACT-2 trial no survival benefit to adding gefitinib given continuously with cisplatin/gemcitabine or with carbopatin/paclitaxel. Erlotinib a quinazoline derivative is a reversible ATP-competitive inhibitor of wild-type EGFR TK and in three large phase III studies the addition of wrlotibnib to carboplatin/paclitaxel(TRIBUTE study) or cisplatin/gemcitabine(TALENT study) showed no survival benefit of improvement as first line therapy. However, erlotinib was shown to prolong survival in NSCLC after first or second-line chemo and received approval in US in Nov 2004. Pao, W. et al. J Clin Oncol; 23:

73 Fig 3. Frequency of epidermal growth factor receptor (EGFR) tyrosine kinase domain mutations detected in non-small-cell lung cancer 192 point mutations detected in NSCLC in exons 18 through 21 of EGFR with 90% occuring in exon 19 as deletions or exon 21 as point mutations. Pao, W. et al. J Clin Oncol; 23:

74 Nat Clin Pract Oncol 2: 554–561 doi:10.1038/ncponc0341
Table 1 Relationship between the presence of EGFR gene mutations and the response to gefitinib and erlotinib treatment in NSCLC patients The close but not exclusive relationship between the presence of mutant EGFR genes and the clinical response to TKIs has been consistently confirmed, but a small but sizable subset of patients with mutations do not respond to TKI therapy while those without the mutation do. Asian studies indicate mutations in exon 19 more sensitive than those in 20 and 21. Giaccone G and Rodrigue JA (2005) EGFR inhibitors: what have we learned from the treatment of lung cancer? Nat Clin Pract Oncol 2: 554–561 doi: /ncponc0341

75 Emerging therapies—targeted therapies for men vs. women
2005 and 2006: Hsieh, Chest 2005;128; female sex and BAC subtype predicted EGFR mutations in NSCLC Veronese, Cancer Invest. 2005;23(4): gefitinib therapy in 112 patients previously failed therapy or poor PS: small study, no gender difference in response Sasaki, Int J Cancer 2006;118: surgically treated NSCLC patients of which 75 adeno ca Total EGFR mutations were in 35 patients and correlated significantly with gender (women 73.3% vs. men 20%); smoking status (69.4% never smokers vs smokers); pathological subtype (45.1% adeno vs. 12.5% non-adeno); and differentiation (51% well vs. 18.4% moderately or poor) One of the issues is that routinely in clinical trials, both the gender (fewer females) and age (less elderly) and race (less blacks) in the US are enrolled making study difficult.

76 Gender differences in behavioral and psychological responses to lung cancer diagnosis and therapy
Overall the prevalence of psychological distress by cancer site is highest in the lung -(Zabora, et al Psycho-Onc 2002;10:19-28) • Ouality of life studies of long term survivors of lung cancer suggest that depression and suicidal ideation is higher in this population (Sarna, 2002;Myrdal, 2003;Uchitomi, 2001,2002,2003) and that female gender may predict psychological distress (Aketchi, 1998;Hopwood, 2000; Kurtz, 2002)

77 86,000 people die annually in the United States from smoking-related chronic obstructive pulmonary disease (COPD), including emphysema and chronic bronchitis • Chronic obstructive pulmonary disease (COPD) includes emphysema and chronic bronchitis, and alpha 1 antitrypsin deficiency-related (ATT) emphysema — diseases that are characterized by obstruction to air flow. • Chronic bronchitis and emphysema are largely smokers’ ailments and they are often present together.1 • A smoker is ten times more likely than a nonsmoker to die of COPD. 1 • 80 to 90% of emphysema cases are caused by smoking.2 • Nearly 16 million Americas suffer from COPD, the fourth leading cause of death in the U.S. • Emphysema causes irreversible lung damage. The walls between the air sacs within the lungs lose their ability to stretch and recoil. They become weakened and break. Elasticity of the lung tissue is lost, causing air to be trapped in the air sacs, impairing the exchange of oxygen and carbon dioxide. 2 American Lung Association Fact Sheet, 1997 1 Lung Disease Data 1997, American Lung Association. 2 Chronic Obstructive Pulmonary Disease, American Lung Association Fact Sheet, August 1997.

78 More than 22 million adult women and at least 1
More than 22 million adult women and at least 1.5 million adolescent girls currently smoke cigarettes. • According to the Centers for Disease Control and Prevention (CDC) Office on Smoking and Health, about 23 million adult women and at least 1.5 million adolescent girls smoke cigarettes, despite what we know about death, disease and addiction caused by smoking.1,2 • Overall smoking prevalence among women aged 18 and older has decreased from 34% in 1965 to 24.7% in However, the earlier trend toward a reduction in smoking by women has leveled off. Currently, it’s estimated that 23% of all American women smoke. • Female smokers typically take up smoking during adolescence, usually before their senior year in high school, often in middle school/junior high. The earlier a young women begins smoking, the more likely she is to be a heavy smoker as an adult.1,3 • Entering adolescence can be a particularly difficult and confusing time for girls. Tobacco advertising and promotion exploits vulnerable young girls’ feelings of insecurity about their identity. Girls who have been aggressive, self-confident, athletic, or who have excelled in school (particularly in math or science) may begin to get messages that these behaviors are not “feminine.” Cigarette ads targeting women depict sexy, attractive, traditionally feminine women. 1 MMWR. 1996;45(27):588-90 Surgeon General’s Report 3 CDC Office on Health and Smoking, 1998

79 Female smokers aged 35 or older are:
• 12 times more likely to die prematurely from lung cancer • 10.5 times more likely to die from emphysema or chronic bronchitis than nonsmoking females. American Lung Association, 1997

80 Each year, more than 150,000 women die from illnesses related to smoking — the most preventable cause of premature death in this country. Other Diagnoses 31,000 Other Cancers 10,000 Other Lung Disease 28,000 Lung Cancer 41,000 Stroke 8,000 Ischemic Heart Disease 34,000 8,000 • Lung cancer deaths attributed to smoking constitute 87% of all lung cancer deaths.1 • Smokers’ risks of heart attack are more than twice that of nonsmokers. Smokers who have heart attacks are more likely to die and die suddenly (within an hour).2 CDC Office on Smoking and Health, 1998 1 Cancer Facts and Figures — American Cancer Society. 2 Risk Factors for Heart Disease, American Heart Association, 1997.

81 Women and COPD Gender Bias in Dx of COPD K Chapman, et al, Chest 2001
Hypothetical case presentation to 192 Primary Care physicians in Canada and US Percentage of Dx offered at each stage of survey DX H/P Spirometry Steroid trial M F M F M F COPD Asthma Other This study suggested that women are more likely to be diagnosed with asthma rather than COPD vs. men at initial presentation to their primary MD. This suggests women may be overlooked when considering COPD. At all three stages asthma was a sig more common alternative dx in the female vs male patient Initial case presentation: COPD was given as probable dx in 58% men vs 42% women p<0.05 Only 22% asked for spirometry

82 Women and COPD Women smokers may be more susceptible to COPD
Y Chen, et al, 1991 E Prescott, et al, 1993 X Xu, et al, 1994 DR Gold, et al, 1996 E Silverman, et al, 2000 Male smokers may be more susceptible to COPD A Camilli, et al, 1987 D Dockery, et al, 1988 Lung Health Study, 1994 Women may be more susceptible to smoking related COPD due to smaller lung size, genetic susceptibility, and other unknown factors. Women with COPD have higher hospitalization rates and possibly increased mortality compared to men.

83 Women and COPD Gender Bias in Dx of COPD K Chapman, et al, Chest 2001
Hypothetical case presentation to 192 Primary Care physicians in Canada and US Percentage of Dx offered at each stage of survey DX H/P Spirometry Steroid trial M F M F M F COPD Asthma Other This study suggested that women are more likely to be diagnosed with asthma rather than COPD vs. men at initial presentation to their primary MD. This suggests women may be overlooked when considering COPD. At all three stages asthma was a sig more common alternative dx in the female vs male patient Initial case presentation: COPD was given as probable dx in 58% men vs 42% women p<0.05 Only 22% asked for spirometry

84 Smoking-Related Cancers
• Bladder • Lung • Cervical • Mouth • Esophageal • Pancreatic • Kidney • Throat • Laryngeal


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