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Sex differences in lung cancer and tobacco-related lung disease: health concerns for women vs. men Cynthia F. Caracta, MD, FCCP Assistant Professor of.

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Presentation on theme: "Sex differences in lung cancer and tobacco-related lung disease: health concerns for women vs. men Cynthia F. Caracta, MD, FCCP Assistant Professor of."— 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

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

4 Denmark 24.9 United Kingdom 20.9 United States 26.3 New Zealand 17.6 Canada , Age Adjusted Per 100,000 Female Death Rates From Lung Cancer A Global Perspective 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 1990s imply that trends in tobacco exposure in young men have been favourable since the early 1980s. –Lung cancer epidemics among women show no consistent pattern that follows those in men either in timing or in relative magnitude.

6 Copyright ©2005 BMJ Publishing Group Ltd. Didkowska, J. et al. BMJ 2005;331: 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. France 7.2% Hungary 6.0% Spain 6.8% UK

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 –Increase in women attributed to increased prevalence of smoking

8 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 Cancer Mortality in the United States: SEER data

9 Copyright ©2005 American Cancer Society From Jemal, A. et al. CA Cancer J Clin 2005;55: Estimated New cases and Estimated New Deaths from Selected Cancers for 2005 in the US

10 Copyright ©2005 American Cancer Society From Jemal, A. et al. CA Cancer J Clin 2005;55: Annual Age-adjusted Cancer Incidence Rates among Males and Females for Selected Cancer Types, US, 1975 to 2001

11 Copyright ©2005 American Cancer Society From Jemal, A. et al. CA Cancer J Clin 2005;55: Annual Age-adjusted Cancer Death Rates Among Females for Selected Cancer Types US, 1930 to 2001

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

13 Cigarette Use Among High School Students 1998 By Grade Level By Gender 33.4%35.3%36.6%39.6% 34.7%37.7%36.4% 9th Grade 10th Grade Females MalesTotal 11th Grade 12th Grade MalesTotal MMWR. 1998;47(SS-3):50.

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%

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 1980s adenocarcinoma surpassed squamous cell: US, Italy, Nordic countries and Japan SEER data RR women : and in men for adenocarcinoma Role of filtered cigarette in the change in histology from central squamous to peripheral adenocarcinomas of the lung

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

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

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 *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. Role of tobacco companies in promoting smoking:

23 Copyright ©2005 BMJ Publishing Group Ltd. Anderson, S J et al. Tob Control 2005;14: 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 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.

24 Copyright ©2005 BMJ Publishing Group Ltd. Anderson, S J et al. Tob Control 2005;14: 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.

25 Copyright ©2005 BMJ Publishing Group Ltd. Anderson, S J et al. Tob Control 2005;14: 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.

26 Copyright ©2005 BMJ Publishing Group Ltd. Anderson, S J et al. Tob Control 2005;14: 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.

27 Copyright ©2005 BMJ Publishing Group Ltd. Anderson, S J et al. Tob Control 2005;14: 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".

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 Repair Cigarette smoking Metabolic Activation eg. Cytochrome P450 Persistence Metabolic Detoxification eg. Glutathione S- Transferase, ExcretionNormal DNA Apoptosis Modified from Hecht JNCI; 1999 Proliferation

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 PAHs, 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 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…

31 modified fromCAPowell 10/2000 DNA adducts and damage in womens 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 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…

32 K-ras proto-oncogene --most mutations reported in smokers 30% from adenocarcinomas 80-90% in codon 12 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… Genes in lung cancer in women: K-ras & p53

33 K-ras and p53 in womens 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…

34 modified from CAPowell 10/2000 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 * > Shriver JNCI 92:24, 2000 mRNA expression in female nonsmokers and short term smokers 55% vs men 0% (p=0.018)

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.

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…

37 Role of estrogen and estrogen receptors in womens 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

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 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 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 cases Stage I NSCLC Found no impact of gender on survival

42 Gender associated differences in presentation, therapy and prognosis of lung cancer 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) Ferguson Ann Thor Sx 2000 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: 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

45 Alexiou, C, et al. European J of Cardiothoracic Sx 2002; 21: 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: Operative Mortality by gender according to procedure: 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 Adapted from Alexiou, C, et al. European J of Cardiothoracic Sx 2002; 21: female male p=0.006

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

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

50 Radzikowska, et al, Annals of Oncology 2002; , 561 patients 17,686 males 2875 females Women were younger smoked less, exhibited more adenoca, and differed in stages.

51 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)

53 Clinical response to lung cancer therapy 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 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

54 Clinical response to lung cancer therapy 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 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

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.

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

58

59

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 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 Keith, B Am J Clin Onc 2002;25: –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 Prophylactic cranial irradiation (PCI) in NSCLC patients

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).

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. OConnell, JP, et al, 1986 Rucksdeschel, JC, et al, 1986 Johnson, BE, et al 1988 Albain, KS, et al, 1991 Paesmans, M, et al, 1995 OConnell, 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, 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 XRT Robnett, TJ, et al, 2000 reported female gender as a risk factor for severe radiation pneumonitis.

66 Adapted from Robnett, TJ, et al, Int. J Rad Onc Biol Phys :89-44 p=0.01 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

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

68 Emerging therapiestargeted 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

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

70

71 Emerging therapiestargeted 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

72 Pao, W. et al. J Clin Oncol; 23: Fig 2. Mutations in the tyrosine kinase (TK) domain of epidermal growth factor receptor (EGFR) associated with sensitivity to gefitinib or erlotinib

73 Pao, W. et al. J Clin Oncol; 23: Fig 3. Frequency of epidermal growth factor receptor (EGFR) tyrosine kinase domain mutations detected in non-small-cell lung cancer

74 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 Table 1 Relationship between the presence of EGFR gene mutations and the response to gefitinib and erlotinib treatment in NSCLC patients

75 Emerging therapiestargeted 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)

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 American Lung Association Fact Sheet, 1997

78 More than 22 million adult women and at least 1.5 million adolescent girls currently smoke cigarettes.

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

80 Each year, more than 150,000 women die from illnesses related to smoking the most preventable cause of premature death in this country. CDC Office on Smoking and Health, ,000 Lung Cancer 41,000 Stroke 8,000 Other Diagnoses 31,000 Ischemic Heart Disease 34,000 Other Lung Disease 28,000 Other Cancers 10,000

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/PSpirometrySteroid 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.

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/PSpirometrySteroid 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.

84 Smoking-Related Cancers BladderLung CervicalMouth EsophagealPancreatic KidneyThroat Laryngeal


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