sex differences in lung cancer and tobacco-related lung disease: health concerns for women vs. men...

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

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

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

Denmark24.9

United Kingdom20.9

United States26.3

New Zealand17.6

Canada22.9

1992-95, Age Adjusted Per 100,000

Female Death Rates From Lung Cancer — A Global Perspective

American Cancer Society, Cancer Facts and Figures, 1998

Global lung cancer mortality

• Didowska, et all BMJ 2005: Lung cancer mortality at ages 35-54 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.

Copyright ©2005 BMJ Publishing Group Ltd.

Didkowska, J. et al. BMJ 2005;331:189-191

Lung cancer mortality in the European Union at age 35-54. 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

Global lung cancer mortality

• Levi, F, et al. E J Cancer Prev 2006: Switzerland, 1980-2001– 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








Cancer Mortality in the United States: SEER data

Copyright ©2005 American Cancer Society

From Jemal, A. et al. CA Cancer J Clin 2005;55:10-30.

Estimated New cases and Estimated New Deaths from Selected Cancers for 2005 in the US



Annual Age-adjusted Cancer Incidence Rates among Males and Females for Selected Cancer Types, US, 1975 to 2001



Annual Age-adjusted Cancer Death Rates Among Females for Selected Cancer Types

US, 1930 to 2001

Smoking in the US and lung cancer








Cigarette Use Among High School Students — 1998

0

10

20

30

40

0

10

20

30

40

By Grade Level By Gender

33.4% 35.3% 36.6% 39.6% 34.7% 37.7% 36.4%

9th Grade

10th Grade

Females

Males Total

11th Grade

12th Grade

Males Total

MMWR. 1998;47(SS-3):50.

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

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%

US smoking prevalence in 2002 by state

Alaska29.3%

Kentucky32.6%

N.Y.22.3%

Utah12.8%

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


– 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?

Changes in lung cancer histology

• 1980’s adenocarcinoma surpassed squamous cell: US, Italy, Nordic countries and Japan

• SEER data 1973-1994 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

Cancer Incidence Rates, US 1973-1996

0

5

10

15

20

25

30

1970- 75- 80- 85- 90-91

Male Adeno Female Adeno

Squamous Male Squamous Female

Source: SEER

Rates per 100,000, age-adjusted

Overall Incidence Incidence: Histology

Copyright ©2005 American Association for Cancer Research

Jemal, A. et al. Cancer Epidemiol Biomarkers Prev 2005;14:582-585

Figure 1. Age-standardized female lung cancer incidence rates for all lung cancers and for two of the four major histologic types (SEER areas, 1973-2001)

* 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:


Anderson, S J et al. Tob Control 2005;14:127-135

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.



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.



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.



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.



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 1997. 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".

The Scheme: From Exposure to Lung Cancer

Repair

N IC O TIN E A D D IC TIO N C A R C IN O G EN Sactive m etabolites

D N A A D D U C TSM IC R O SA TELLITE IN STA B ILITY

M U TA TIO N S, etcp53, k-ras, LO H

L U N GC A N C E R

Cigarette smoking

Metabolic Activation eg. Cytochrome P450

Persistence

Metabolic Detoxification

eg. Glutathione S-Transferase,

Excretion Normal DNA

Apoptosis

Modified from Hecht JNCI; 1999

Proliferation

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…

modified fromCAPowell 10/2000

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

4/11

0/11

1/11

6/11

8/37

12/3711/37

6/37

0.00

0.10

0.20

0.30

0.40

0.50

0.60

1 2 3 4

Quartile group of adducts/packyear

perc

ent

Female

Male

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…

• K-ras proto-oncogene --most mutations reported in smokers30% from adenocarcinoma’s 80-90% in codon 12 GT 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

K-ras and p53 in women’s lung cancer• P53 tumor supressor gene mutations occur in

regions between exons 4 and 8 -- GT 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…

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

0

0

55

1-25

20

75*

26-49

75

70

> 50

59

69

Shriver JNCI 92:24, 2000

mRNA expression in female nonsmokers and short term smokers

55% vs men 0% (p=0.018)

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.

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…

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

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?

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

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 1999428 patient case control studyFound age, histology, and

stage influenced prognosisWomen more adeno: men

more squamous caWomen had 2.1 x increased

long-term survivalNo difference in tx received• Suzuki Cancer 1999 430 cases Stage I NSCLCFound no impact of gender on

survival

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

Ferguson, MK, et al, Ann Thoracic Surg 2000;69:245-50

Women were younger, smoked less, slightly higher Stage I distribution, and similar distribution of resection extent and operative mortality as compared to men.

Ferguson, MK, et al, Ann Thoracic Surg 2000;69:245-50

Alexiou, C, et al. European J of Cardiothoracic Sx 2002; 21:319-325

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.

Alexiou, C, et al. European J ofCardiothoracic Sx 2002; 21:319-325

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.

Adapted from Alexiou, C, et al. European J of Cardiothoracic Sx 2002; 21:319-325

female

male

male

p=0.006


female

male

p=0.01


female

male

pP

p=0.002

Radzikowska, et al, Annals of Oncology 2002;131087-1093

20, 561 patients17,686 males2875 females

Women were youngersmoked less, exhibitedmore adenoca, and differed in stages.

Table 2. Clinicopathological characteristics of lung cancer patients

All (%) Female

Male

P value

No.

%

No.

%

Age (years) 20 561 <0.001

<50 2902 (14.1) 671 23.3 2231 12.6

>50 17 659 (85.9) 2204 76.7 15 455 87.4

Smoking 20 561 <0.001

Smokers 16 327 (95.7) 1659 81.2 14 668 97.6

Non-smokers 738 (4.3) 385 18.8 353 2.4

Histology 16 791 <0.001

Adenocarcinoma 1881 (11.3) 505 21.6 1376 9.6 <0.001

SCLC 3479 (20.8) 620 26.6 2859 19.9 <0.001

Squamous 8705 (52.1) 759 32.5 7946 55.2 <0.001

Other 2654 (15.8) 450 19.3 2204 15.3 <0.001

Performance status 15 212 0.349

0/1 8737 (57.4) 1251 58.8 7486 57.2 NS

2 4687 (30.8) 622 29.2 4065 31 NS

3/4 1788 (11.8) 254 12 1534 11.8 NS

Clinical stage 12 794 0.03

I 3476 (27.2) 512 27.1 2964 27.1 NS

II 1884 (14.7) 230 12.2 1654 15.2 0.03

III 5541 (43.3) 764 40.5 4777 43.8 0.03

IV

1893 (14.8)

380

20.3

1513

13.9

0.001

NS, not significant.

Adapted from Radzikowska, et al, Annals of Oncology 2002;131087-1093

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)

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 1974-1978 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

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

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.

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

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

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

The solitary brain met in lung cancer

• 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

Prophylactic cranial irradiation (PCI) in NSCLC patients

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).

Gender differences in response to therapy for advanced NSCLC lung cancer

Clinical studies for unresectable or medically inoperable NSCLCsuggest women have an increased survival after treatment withchemotherapy and XRT over men.

O’Connell, JP, et al, 1986Rucksdeschel, JC, et al, 1986Johnson, BE , et al 1988Albain, KS, et al, 1991Paesmans, M, et al, 1995 O’Connell, JP, et al, 1996

Ramalingam, S, et al, 1998Jirontek, M et al, 1998Jeremic, B et al, 2003

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 1983-1984

– 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 - 150 Stage I-IIIB treated with XRT 1991-1998 - younger, high PS, female gender prolonged survival

Gender differences in response to therapy for advanced NSCLC lung cancer and XRT tx

XRT

Robnett, TJ, et al, 2000reported female gender as a risk factor for severeradiation pneumonitis.

Adapted from Robnett, TJ, et al, Int. J Rad Onc Biol Phys 2000 48:89-44

p=0.01p=0.01

The probability of severe radiation pneumonitis as a function of gender performance status:

Combined female genderand performance status PS-1strongly associated with severeradiation pneumonitis

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, 1989Wolf, M et al, 1991Albain, KS, et al, 1991Tas, F, et al, 1999Paesmans, M, et al, 2000

Janne, PA, et al, 2002Christodolou, C, et al, 2002Naughton, MJ, et al 2002Bremnes, RM, et al, 2003

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

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


• 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; non smokers, Japanese origin, adeno ca

especially bronchioalveolar carcinoma

Copyright © American Society of Clinical Oncology

Pao, W. et al. J Clin Oncol; 23:2556-2568 2005

Fig 2. Mutations in the tyrosine kinase (TK) domain of epidermal growth factor receptor (EGFR) associated with sensitivity to gefitinib or erlotinib

Copyright © American Society of Clinical Oncology

Pao, W. et al. J Clin Oncol; 23:2556-2568 2005

Fig 3. Frequency of epidermal growth factor receptor (EGFR) tyrosine kinase domain mutations detected in non-small-cell lung cancer

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:10.1038/ncponc0341

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


• 2005 and 2006:– Hsieh, Chest 2005;128;317-321 female sex and BAC

subtype predicted EGFR mutations in NSCLC– Veronese, Cancer Invest. 2005;23(4):296-302 gefitinib

therapy in 112 patients previously failed therapy or poor PS: small study, no gender difference in response

– Sasaki, Int J Cancer 2006;118:180-184 95 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. 16.9 smokers); pathological subtype (45.1% adeno vs. 12.5% non-adeno); and differentiation (51% well vs. 18.4% moderately or poor)

Gender differences in behavioral and psychological responses to lung cancer

diagnosis and therapy

• Overall the prevalence of psychologicaldistress 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)

86,000 people die annually in the United States from smoking-related chronic obstructive pulmonary disease (COPD), including emphysema and chronic bronchitisAmerican Lung Association Fact Sheet, 1997

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

• 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.

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, 1998

8,000

Other Diagno

ses

Lung Cancer41,000

Stroke8,000

Other Diagnoses31,000

Ischemic Heart Disease 34,000

Other Lung Disease

28,000

Other Cancers10,000

Women and COPD• Gender Bias in Dx of COPD

– K Chapman, et al, Chest 2001Hypothetical case presentation to 192 Primary Care physicians

in Canada and USPercentage of Dx offered at each stage of survey

DX H/P Spirometry Steroid trial M F M F M F

COPD 64.6 49 76 64 85.4 78.1Asthma 32.3 43.8 21.9 32.3 10.4 17.7Other 3.1 7.3 2.1 3.1 4.2 4.2

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.

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 tosmaller lung size, genetic susceptibility, and other unknown factors.Women with COPD have higher hospitalization rates and possibly increased mortality compared to men.

Women and COPD• Gender Bias in Dx of COPD

– K Chapman, et al, Chest 2001Hypothetical case presentation to 192 Primary Care physicians

in Canada and USPercentage of Dx offered at each stage of survey

DX H/P Spirometry Steroid trial M F M F M F

COPD 64.6 49 76 64 85.4 78.1Asthma 32.3 43.8 21.9 32.3 10.4 17.7Other 3.1 7.3 2.1 3.1 4.2 4.2

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.

Smoking-Related Cancers

• Bladder • Lung• Cervical • Mouth• Esophageal • Pancreatic• Kidney • Throat• Laryngeal

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cancer facts

lung cancer epidemics

histology of lung cancer

cancerrelated deaths

male lung cancer mortality

selected cancer types