no specific (“gender driven”) diagnostic approach is...

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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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N trials: 39N pts: 86800% ♀: 37.7%



N trials: 39N pts: 86800% ♀: 37.7%


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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


• 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


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• 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


• 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

no specific (“gender driven”) diagnostic approach is...

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