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Gender Issues in Lung Cancer
Silvia NovelloUniversity of [email protected]
www.womenagainstlungcancer.eu
NO specific (“gender driven”) diagnosticapproach is nowadays available
NO specific (“gender driven”) therapeutic approach is nowadays available
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Lung cancer mortality in European women: Trends and predictions
Current Trends in Austria
Bosetti C, Malvezzi M et al Lung Cancer 2012
Thompson CA The Central EuropeanJournal of Medicine, 2012
Cancer Mortality in Italy
MEN WOMEN20082008
Cancer Deaths registered 97,773 144.1/100,000
7501084.3/100,000
Lung Cancer (all ages) 25,366 *37.7/100,000
7,743°9.5/100,000
Projection to 2012Cancer Deaths 100.000 78,000
132,5/100,000 80.5/100,000Lung Cancer (all ages) -
33.3 /100,0008,500§
9.8/100,000
Malvezzi M et al, Tumori May 2012
*leading cause for all ages accounting for over 25% of all male cancer deaths ,°after breast and intestines §becoming second cause
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US: Increasing Lung Cancer Death Rates Among Young Women in Southern and Midwestern States
A: CaliforniaB: New YorkC: Alabama
Jemal A et al, JCO Aug 2012
Gender differences in life expectancy in Korea (’70-2005)
Yang S et al; Social Science & Medicine, May 2012
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Lung Cancer Prognosis in Spain
28.7%16.8%
Salmeron D et al, Respiratory Medicine (2012) 106, 1301e1308
Cases diagnosed with lung cancer during the period 1995-1999 were followed up until December 31, 2004 in 7 region (15% Spain population).
Lung Cancer Prognosis in Spain
Salmeron D et al, Respiratory Medicine (2012) 106, 1301e1308
Cases diagnosed with lung cancer during the period 1995-1999 were followed up until December 31, 2004 in 7 region (15% Spain population).
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Better Outcome for Females ? …….not only in Lung
• Colorectal cancer: DFS and OS longer for women afterti ( )resection (Wichmann BJC, 2001)
• Gastric Cancer: longer survival for women after gastrectomyand chemotherapy (Tas Am J Clin Oncol, 2000)
• Esophageal cancer: longer survival for women after chemo-and radiotherapy (Lim Int J Radiat Oncol Biol Phys, 2003)
• Malignancies in Young Adults: male AYAs experienced lesstoxicity and lower response rates to chemotherapy (p 0.008) (Khamly KK Int J Cancer, 2009)
Female Gender as independent Prognostic Factor in NSCLC: a Meta-analysis
N trials: 39N pts: 86800% ♀: 37.7%
Nakamura H et al, Ann Thorac Cardiovasc Surg 2011
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Female Gender as independent Prognostic Factor in NSCLC: a Meta-analysis
N trials: 39N pts: 86800% ♀: 37.7%
Nakamura H et al, Ann Thorac Cardiovasc Surg 2011
Female Gender as independent Prognostic Factor in NSCLC: a Meta-analysis
N trials: 39N pts: 86800% ♀: 37.7%
Nakamura H et al, Ann Thorac Cardiovasc Surg 2011
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Impact of Cigarette Smoking on Cancer Risk in Europe
(TRC
)
N= 441,211TRC=14,563Follow-up=11yrs
Agudo A et al, JCO Dec 2012
[AFp= population attributable fraction using the adjusted hazard ratios and 95% CI for current and former smokers, plus either the prevalence of smoking among cancer cases or estimates from surveys in representative samples of the population in each country]
Funatogawa I et al, BMJ Open Sept 2012
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Women’s attitudes regarding tobacco control policies
N=5000 (2935 never smoker) Czech Republic France Czech Republic, France,Ireland, Italy, and Sweden June-July 2008 The largest proportionsof women were >55 year age
Dresler C et al, Scandinavian Journal of Public Health Sept 2012
Women’s attitudes regarding tobacco control policies
N=5000 (2935 never smoker) Czech Republic France
“New tobacco control laws would prompt smokers to quit” Czech Republic, France,
Ireland, Italy, and Sweden June-July 2008 The largest proportionsof women were >55 year age
would prompt smokers to quit
AGREEMENT:
46.8% Ireland43.6% Sweden30 5% F
Dresler C et al, Scandinavian Journal of Public Health Sept 2012
30.5% France20.9% Italy15.1% Czech Republic
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Weight for Height in Relation to Risk of Cancer in Canadian Women
Kabat GC et al, American Journal of EpidemiologyFeb 2012
Risk of lung cancer associated with domestic use of coal in China
N=37.272
Barone-Adesi F et al, BMJ Aug 2012
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Risk of lung cancer associated with domestic use of coal in China
N=37.272
Barone-Adesi F et al, BMJ Aug 2012
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Genome-wide association lung cancer susceptibility loci in never-smoking women in Asia
Lan Q et al, Nature Genetics Nov 2012
Never Smokers
NOT evaluated
- Diet- Outdoor air pollution- Occupational Exposures- High-temperature frying- Pneumonia in Europe/China
J Sisti, P Boffetta, Int J Cancer 20
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Radon in Never Smokers (Spain)variable N (%)
SexFemaleMale
58 (84.1%)11 (15.9%)
Adenocarcinoma 56 (81%)Adenocarcinoma 56 (81%)
Age at diagnosisMean (95% CI) 68.6 (65.8–71.4)
[25% diagnosed ≤60yrs]
Concentration of residential radon (Bq/m3) in the cases included
Mean (95% CI) 266 (227–304)
A. Ruano-Ravina et al., Arch Bronconeumol. 2012
CBMN to detect genetic instability
• Genetic instability and risk of lung cancer associated with exposure to environmental agents and smoking (500 cases and 500 controls)environmental agents and smoking (500 cases and 500 controls)
• DNA damage was measured using the cytokinesis-blocked micronucleus (CBMN) assay in human lymphocytes
• Significantly higher levels of micronuclei and nucleoplasmic bridges as compared with controls
• A difference in lung cancer risk was observed between nonexposed male and female heavy smokers
• Heavy smoking may have an effect on DNA repair capacity and in turn modulate the risk of lung cancer.
McHugh MK et al, Cancer Epidemiol Biomarkers Prev Nov 2012
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RT mortality from heart disease and lung cancer after radiotherapy for breast cancer
N=558 871 (45.8%b right, 46.2% left)
Henson KE et al, BJC Dec 2012
RT mortality from heart disease and lung cancer after radiotherapy for breast cancer
N=558 871 (45.8%b right, 46.2% left)
Henson KE et al, BJC Dec 2012
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Risk of a second primary lung cancer after a first invasive breast cancer according to ER status
ER negative ER positive
Women 50,781 171,367
RT for breast 27,367 99,382
Lung Cancer 418(SIR 1.20)
1444(SIR 0.96)
Time since breast cancer diagnosis1-<55-9≥10
24412252
672550222
Age at breast cancer diagnosis<5050-5960-69≥70
6612915766
134341661308
12 SEER registries, 1992–2008Schonfeld SJ et al, Cancer Causes Control Aug 2012
Gender and EGFR mutationsNo mutation detected
KRAS (22%)
EGFR (18%)
EML4-ALK (7%)
Double mutants (2%)
BRAF (2%)
AKT1
NRAS<1%
MEK1<1%
HER2 1%
PIK3CA 1%
MET AMP<1%
Shepherd F et al, NEJM 2005
Johnson , et al.,ECCO ESMO 2011. Abstract 9018.
Tanaka T et al, Int J Cancer 2010
p< 0.047
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Phase II trial of gefitinib in pretreated Chinese women with advanced NSCLC
PFS =13 months(95% CI: 8.0–17.9)
OS=20 months (95% CI: 11.9–28)
Deng J et al, Med Oncol; March 2011
70% surviving 1 year; 32.5% surviving 2 years
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Gender and KRAS MutationNo mutation detected
KRAS (22%)
EGFR (18%)
EML4-ALK (7%)
Double mutants (2%)
BRAF (2%)
AKT1
NRAS<1%
MEK1<1%
HER2 1%
PIK3CA 1%
MET AMP<1%
Johnson et al
Nelson HH, J Natl Cancer Res 1999
Johnson , et al.ECCO ESMO 2011. Abstract 9018.
Gender and KRAS MutationNo mutation detected
KRAS (22%)
EGFR (18%)
EML4-ALK (7%)
Double mutants (2%)
BRAF (2%)
AKT1
NRAS<1%
MEK1<1%
HER2 1%
PIK3CA 1%
MET AMP<1%
Johnson et al
KRAS mutation type as a function ofsmoking history
Johnson , et al.ECCO ESMO 2011. Abstract 9018.
Riely GJ, Clin Cancer Res 2008
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Gender and Alk TranslocationNo mutation detected
KRAS (22%)
EGFR (18%)
EML4-ALK (7%)
Double mutants (2%)
BRAF (2%)
AKT1
NRAS<1%
MEK1<1%
HER2 1%
PIK3CA 1%
MET AMP<1%
Johnson D et al
1. Camidge et al., ASCO 2011; Abs #25012. Riely et al., IASLC 2011; Abs #O31.05
Johnson D, et al.ECCO ESMO 2011. Abstract 9018.
Response by Pts
Characteristics
Gender and Braf mutationsNo mutation detected
KRAS (22%)
EGFR (18%)
EML4-ALK (7%)
Double mutants (2%)
BRAF (2%)
AKT1
NRAS<1%
MEK1<1%
HER2 1%
PIK3CA 1%
MET AMP<1%
Johnson D, et al.ECCO ESMO 2011. Abstract 9018Abstract 9018.
Marchetti A et al, JCO 2011MELANOMA
Paik PK et al, JCO 2011ADENOCARCINOMA
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Gender and Braf mutationsNo mutation detected
KRAS (22%)
EGFR (18%)
EML4-ALK (7%)
Double mutants (2%)
BRAF (2%)
AKT1
NRAS<1%
MEK1<1%
HER2 1%
PIK3CA 1%
MET AMP<1%
Johnson D, et al.ECCO ESMO 2011. Abstract 9018Abstract 9018.
Marchetti A et al, JCO 2011
• DNA repair capacity• DNA repair capacity
Some Suggested Explanations
to support Gender Differences
• DNA repair capacity
• Gender differences in metabolism of carcinogens
• Differences in proliferation/growth stimulation (GRPR)
• DNA repair capacity
• Gender differences in metabolism of carcinogens
• Differences in proliferation/growth stimulation (GRPR)
• Hormonal interactions• Hormonal interactions
Lung Cancer Fourth Edition, Gender-Related Differences in Lung CancerNovello S, Brahmer JR, Stabile LP, Siegfried JM
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β-estradiol induces
Hormonal Interactions
proliferation in NSCLC cells and anti-estrogensblock this effect
Kiuper, Endocrinology 1997
Oestrogens may be involved in lung tumorigenesis at different levels:Oestrogens may be involved in lung tumorigenesis at different levels:• As ER ligands activating cell proliferation• Via ERs in the plasma membrane causing interactions between ERs and
growth factors such as EGF and IGF (in EGFR and ER+ cells)• Oestrogens may alter metabolic activation of carcinogens (modulations
of CY1A1, CY1B1) Stabile L; Cancer Res 2005
References Methodology N Principal FindingsAbe K, 2010 IHC 105 ER expression was associated with aromatase
expression in NSCLC
Schwartz G; Wu CT; 2005; Skov BG, 2008
IHC 278/301/104
ER expression was associated with better clinical outcome in NSCLC
Niikawa H, 2008 IHC 59 Aromatase expression was associated with intratumoral
Studies on ERs in Neoplastic Lung Disease
, pEstradiol conc. in NSCLC
Raso MG, 2009 IHC 317 ER expression was associated with EGFR mutations in NSCLCs
Hershberger PA, ’05, ‘09; Jarzynka MJ 2006
in vitro(NSCLCcell lines)
- ER demonstrated tumor promoting features in the absence of ER
Hammoud Z 2008; Jarzynka MJ 2006; Stabile L 2005
in vivo(mouse)
- Estradiol stimulated the growth of lung carcinoma xenografts
Mah V, 2007 IHC 442 Lower levels of aromatase predicted a better survival in females above 65
Márquez-Garbán DC ‘09; Weinberg OK ,’05
in vitroin vivo
- Aromatase inhibitor (AI) suppressed the lung tumor growth
Issa JP, 1996 Southernblot
46 Pts with a history of smoking had a significantly lower incidence of ER promoter methylation than non-smokers in lung tumors
M.K. Verma et al., Journal of Steroid Biochemistry & Molecular Biology 127 (2011) 216– 222
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“Hormonal Factors” and Lung Cancer Risk: A Meta-analysis
Zhang Y et al, Chin J Lung Cancer, December 2012
older age at menarche in North America women RR=0.83; 95%CI: 0.73-0.94
Cases %(N=407)§
Controls % (N=499)§
*Model 1OR (95% CI)
p **Model 2OR (95% CI)
p
Age at first livebirth2222-2526-30≥31
20.431.335.312.5
12.729.740.217
10.92 (0.54–1.56)0.77 (0.46–1.29)0.57 (0.31–1.06) 0.05
10.95(0.31–1.06)0.73 (0.42–1.27)0.52 (0.26–1.01) 0.03
Age at menopause<4646-51≥51
25.833.624.4
18.033.238.7
10.65 (0.41–1.02)0.49 (0.31–0.79) 0.003
10.70 (0.43–1.14)0.51 (0.31–0.84) 0.01
Reproductiveduration<3333–36
26.324.1
20.431.2
10.77 (0.48–1.24)
10.84 (0.51–1.40)
37-40≥41
24.110.1
16.713.8
0.67 (0.43–1.06)0.44 (0.25–0.79) 0.01
0.76 (0.47–1.25)0.46 (0.25–0.85) 0.02
Pesatori AC et al, Int J Cancer 2012
§ some missing data; *adjusted for area, age at study, smoking (ever/never, pack-years, time since quitting); **: adjusted for area, age at study,smoking (ever/never, pack-years, time since quitting), ETS, education, BMI.
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Reference Type of study N Risk of lung Ca with HRT 95% CI
Taioli, JNCI, 1994
Case control 180 1.7 1.0-2.8
Ad I t J C
Hormone Replacement Therapy (HRT) and Lung Cancer Risk
Adams,Int J Cancer, 1989 Cohort study 23,244 1.3 0.9-1.7
Wu, Cancer Res, 1998 Case control 336 1.3 0.71-1.53
Women's Health Initiative, JAMA, 2002 Cohort 16,690 1.04 0.71-1.53
Blackman, PharmacoepidemiolDrug Saf, 2002
Case Control 662 1.0 -=
Ettinger, Ob Gynecol, 1996 - 454 0.78 0.04-1.15
Kreuzer, 2003 Case control 1723 0.83 0.64-1.09
Olsson, Ob Gyne, 2003 Cohort 29,508 0.24 0.08-0.76
Schabath, Clin Ca Res, 2004 Case Control 1008 0.66 0.51 - 0.89
HRT and Survival in ♀ with Lung Cancer
Ganti AK et al, JCO 2006
• N= 498 ♀: HRT 17%, smokers 86%, NSCLC 76%• OS is longer in pts who had never used HRT (79 v 39months, respectively; HR1.97; 95% CI, 1.14 to 3.39)• This effect seemed to be more pronounced in women with a smoking history
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Estrogen: Therapeutic Implications
Bouchardy C et al , Cancer 2011
Decreased Cell Proliferation in Lung Tumors Treated with Gefitinib and Fulvestrant
sio
n
100
120
ela
tive
Ki6
7 E
xpre
ss
20
40
60
80
100
*
**
**
Re
0
Treatments
control fulvestrant fulvestrant +gefitinib
gefitinib
Stabile, et al. Cancer Res, 2005
P-value compared to control: *<0.05, **<0.005
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UW/UPitt Pilot Study of Gefitinib + Fulvestrant in Post-menopausal Women with Advanced Recurrent NSCLC
Eli ibilit 2 i h i• Eligibility: 2 or more prior chemo regimens• Treatment: 250 mg gefitinib + 250 mg fulvestrant IM
monthly• Objectives: response rate, TTP, survival• Laboratory Objectives:• Laboratory Objectives:
- ER and EGFr- CYP3A polymorphisms
Traynor AM, Schiller J, Lung Cancer 2009
UW/UPitt Pilot Study of Gefitinib + Fulvestrant in Post-menopausal Women with Advanced Recurrent NSCLC
• Twenty patients were evaluable for response: three partial responses (PRs) were confirmed (15%, 95% CI: 5–36%).
• Median PFS= 12 wks, OS=38.5 wks, estimated 1-year OS= 41% • Survival outcomes did not differ by prior lines of therapy
Traynor AM, Schiller J, Lung Cancer 2009
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UW/UPitt Pilot Study of Gefitinib + Fulvestrant in Post-menopausal Women with Advanced Recurrent NSCLC
• Twenty patients were evaluable for response: three partial responses (PRs) were confirmed (15%, 95% CI: 5–36%).
Ongoing Trials
• Phase II trial evaluating addition of Fulvestrant to erlotinib in patients withstage IIIb/IV non-small cell lung cancer (NSCLC) who are stable on erlotinib and
• Median PFS= 12 wks, OS=38.5 wks, estimated 1-year OS= 41% • Survival outcomes did not differ by prior lines of therapy
exhibit IHC or PCR positivity for estrogen or progesterone receptor .Bazhenova L, et al. Abstr TPS292
• Randomized phase II erlotinib alone or in combination with Fulvestrant inpreviously treated patients with advanced non-small cell lung cancer.Garon EB, et al. Abstr TPS293
Traynor AM, Schiller J, Lung Cancer 2009
• Fulvestrant and Anastrozole as Consolidation Therapy in PostmenopausalWomen With Advanced Non-small Cell Lung Cancer PI Ahmad Tarhini;NCT00932152
Conclusions• A better understanding of the genetic, metabolic, and hormonal
factors in women represents a research priority. Many contradictory data about this item are present in literature, underlying that we need confirmatory prospective dataunderlying that we need confirmatory prospective data.
• Evidence suggests that the development of lung cancer is different in women compared with men
• Women with lung cancer live longer than men with lung cancer, regardless of therapy and stageregardless of therapy and stage
• Sex as stratification factor is useful in prospective clinical trials
• No specific and “gender driven” therapeutical approaches are already available