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Studies in NSCLC Based on Gender and Smoking Differences: Rationale and Outcomes Silvia Novello University of Turin Thoracic Oncology Unit. www.oncologiapolmonare.it silvia.novello@unito.it www.womenagainstlungcancer.eu silvia.novello@womenagainstlungcancer .eu. 100. 80. 60. 40. 20. 0.

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slide1

Studies in NSCLC Based on Gender and Smoking Differences: Rationale and OutcomesSilvia Novello University of Turin Thoracic Oncology Unit

www.oncologiapolmonare.itsilvia.novello@unito.it

www.womenagainstlungcancer.eu

silvia.novello@womenagainstlungcancer.eu

slide2

100

80

60

40

20

0

Annual Age-Adjusted Cancer Death Rates Among Males/Females

for Selected Cancer Types, US, 1930-2004

100

Females

Males

Colon & Rectum

Lung & Bronchus

Stomach

Stomach

Ovary

Colon & Rectum

80

Uterus

Prostate

Breast

Liver

Lung & Bronchus

Leukemia

Lung & Bronchus

Pancreas

Pancreas

60

Rate per 100,000 Females

Rate per 100,000 Males

Lung & Bronchus

40

20

0

1930

1970

1990

2004

1930

1970

1990

2004

1950

1950

Year of Death

Year of Death

CA Cancer J Clin 2004; 54:9-15

model of smoking epidemic
Model of Smoking Epidemic

Smoke kills about 50% of smokers: there are 3-4 decades between prevalence peak and mortality peak for lung cancer

Lopez et al, Tobacco Control 1994

lifetime probability of developing cancer 1997 2001
Lifetime Probability of Developing Cancer1997-2001

SiteRisk

Site Risk

All sites 1 in 2

Prostate 1 in 6

Lung & bronchus 1 in 13

All sites 1 in 3

Breast 1 in 7

Lung & bronchus 1 in 18

ACS, 2005

slide5

Meta-Analysis of 28 Lung Cancer Studies*

Relative Risk Ratios for Ever Smokers

Relative Risk Ratio

Histology

* 27 case-control

Khuder, Lung Cancer, 2001

women and lung cancer risk smokers vs non smokers
Women and Lung Cancer Risk(smokers vs non-smokers)

Author Study Men Women n.cigarettes

Risch case- 9.6 27.9 40 packs/yr

Am J Epidemiol ’93 control

Zhang case- 11.6 21.4 40 packs/yr

J Natl Cancer Inst ’96 control

Harris case- 24.5 42 40 packs/yr

Int J Epidemiol ’93 control

Bach cohort no difference

J Natl Cancer Inst ’03

Bain cohort no difference

J Natl Cancer Inst ‘04

women and lung cancer
Women and Lung Cancer
  • Female smokers are more likely to develop adenocarcinoma
  • than squamous cell carcinoma
  • Thun MJ et al:JNCI 1997; Fu JB et al: Chest 2005; Patel JD et al: JCO 2005
  • The BAC is two to four times more common among women
  • than among men
  • Thun MJ et al:JNCI 1997; Radzikowska E et al: Ann Oncol 2002; Fu JB et al: Chest 2005
  • Never-smokers with lung cancer have adenocarcinoma and
  • are 2.5 times more likely to be females than males
  • Wong MP et al: Cancer 2003
  • In some Asian countries never-smokers account for 70%
  • of women with lung cancer Wong MP et al: Cancer 2003
slide9

Some Suggested Explanations

  • DNA repair capacity
  • Gender differences in metabolism of carcinogens
  • Differences in proliferation/growth stimulation (GRPR)
  • Hormonal interactions
slide10

DNA Repair Capacity

Host Cell Reactivation Assay

+ .Acetyl CoA

+ Chloramphenicol

+ .Acetyl CoA

+ Chloramphenicol

Acetyl -Chloramphenicol

Benzo[a]pyrene

Test

Lymphocytes

slide11

DRC and Risk of Lung Cancer

Variable AdjustedOR (95% CI)

DRC (median) > 8.1 1.0 < 8.1 1.5 (1.2, 1.9)

Smoking Status

Never 1.8 (1.0, 3.3)

Former 1.4 (1.0, 1.9)

Current 1.6 (1.2, 2.3)

n = 764 cases and 677 controls

Spitz et al, CEBP, 2003

slide12

DNA Repair Capacity

Lung Cancer Cases

Variable No Mean % p-value SD for trend

Age (years) < 60 128 7.6 ± 2.8

60 - 69 123 8.2 ± 3.2 0.05

 70 65 8.5 ± 3.2

GenderMale 402 8.2 ± 2.8 < 0.001 Female 362 7.5 ± 2.8

Spitz, CEBP, 2003

slide13

Induced Adduct Levels

Lung Cancer Cases

Variable NMean(%)SD P value

Age (yrs)

< 60 109 100.8 ± 94.6 0.05

61+112 85.8 ± 83.6

Gender

Male 114 100.1 ± 89.1 NS Female 107 85.8 ± 89.4

Smoking statusNever 21 103.7 ±101.6 NS Former 85 87.1 ± 75.0Current 115 95.8 ± 97.0

Li et al, Cancer Res 2001

gender differences in metabolism of carcinogens cyp1a1
Gender differences in metabolism of carcinogensCYP1A1
  • CYPA1 codes for an enzyme which activates PAH-forming DNA adducts.
  • Significant correlation between CYP1A1 expression and DNA adduct levels (r= 0.50, p= 0.016)
  • Female smokers had significantly higher levels of adducts/pack-year and adducts/cigarette/day than men (1.49 + 1.29 vs. 0.89 + 0.74, P= 0.015)
  • Females had higher CYP1A1 levels than males (494 + 334 units vs. 210 + 208 units, P= 0.016)

Mollerup, et al; Cancer Res; 1999: 59: 3317-20

gender differences in metabolism of carcinogens glutathione s transferase gst
Gender differences in metabolism of carcinogensGlutathione S-transferase (GST)
  • GST deactivates carcinogens; the null genotype fails to deactivate carcinogens, resulting in prolonged exposure
  • GSTM1 null genotype associated with lung cancer (odds ratio: 2.04)

Tang, et al; Carcinogenesis, 19: 1949-1953, 1998

slide16

Differences in proliferation/growth stimulation

GRP

  • Gastrin-Releasing Peptide (GRP): plays a role in neoplasia
  • by stimulating cell proliferation. Its effect is mediated mainly
  • through the GRPR.
  • The gene for GRPR is X-linked, located on chromosome
  • Xp22, near a cluster of genes that escape X-inactivation.
  • Women can have two actively transcribed alleles compared
  • with only one in men
  • Increased expression of the GRPR gene was noted when
  • human airway cells were exposed to oestrogens.

Shriver SP 2000, JNCI

hormonal interactions
Hormonal Interactions
  • Early age at menopause (≤ 40 yrs) is associated with reduced risk of lung adenocarcinoma (OR=0.3)
  • HRT is associated with  risk of adenocarcinoma (OR=1.7)
  • Interaction between HRT, smoking and the development of lung adenocarcinoma (OR=32.4)

Taioli and Wynder:JNCI 1994

  • Late menopause and short menstrual cycles were associated with increased risk of lung cancer

Siegfried JM: The Lancet Oncology 2001

  •  risk of lung carcinoma in women with family history of reproductive cancer

Sellers: Genetic Epidem 1991

slide19

Hormonal Interactions

β-estradiol induces

proliferation in NSCLC cells and anti-estrogens block this effectKiuper, Endocrinology 1997

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: Cancer Res 2005
cross talk cascade of er activation

Basal

Transcription

Machinery

P

P

P

p160

CBP

ER

ER

ERE

ER Target Gene Transcription

Growth factors

Cross-Talk Cascade of ER Activation

Estrogen

IGFR

Tamoxifen

EGFR / HER2

MoAb

Plasma

Membrane

P

P

P

P

P

SOS

P

TKI

RAS

PI3-K

FTI

RAF

Cell

Survival

Akt

SERD

P

MEK

AI

CCI

P

ER

p90RSK

MAPK

P

P

Cytoplasm

Cell

Growth

P

Nucleus

Johnston, S. 2004

slide21

Decreased Cell Proliferation in Lung Tumors Treated with Gefitinib and Fulvestrant

120

100

80

*

Relative Ki67 Expression

**

60

**

40

20

0

control

fulvestrant

gefitinib

fulvestrant +

gefitinib

Treatments

P-value compared to control: *<0.05, **<0.005

Stabile, et al. Cancer Res, 2005

uw upitt pilot study of gefitinib faslodex in post menopausal women with advanced recurrent nsclc
UW/UPitt Pilot Study of Gefitinib + Faslodex in Post-menopausal Women with Advanced Recurrent NSCLC
  • Eligibility: 2 or more prior chemo regimens
  • Treatment: 250 mg gefitinib + 250 mg Faslodex IM monthly
  • Objectives: response rate, TTP, survival
  • Laboratory Objectives:

- ER and EGFr

- CYP3A polymorphisms

Traynor AM, Schiller J, JCO 2005

hormone replacement therapy and lung cancer risk
Hormone Replacement Therapy and Lung Cancer Risk

Some positive

  • All studies derived from secondary data or exploratory analysis
hormone replacement therapy and lung cancer risk24
Hormone Replacement Therapy and Lung Cancer Risk

Some show no increase in risk

All studies derived from secondary data or exploratory analysis

hormone replacement therapy and lung cancer risk25
Hormone Replacement Therapy and Lung Cancer Risk

Some show REDUCED risk of lung cancer with HRT

All studies derived from secondary data or exploratory analysis

sex as a predictive factor
Sex as a predictive factor

Study N Unfavorable in

Multivariate Analysis

Radzikowska (1995-98) 20,561 Male, poor PS, advanced

Polish population, all stage, non surgical treatment,

>50 yrs, SCLC

Ouellete (1988-90) 208 Male, advanced stage

French population, cohort

Moore (1974-98) 7,613 Male, age >65, advanced

Single institution, all stage, large cell, no surgery

Visbal (1997-2000) 4,618 Male, older age, high grade,

Single institution, advanced stage, treatment,

consecutive cohort adenocarcinoma*

Relative risk (RR) of death for MEN = 1.15 (p=0.001)

NO differences in overall mean survival

BUT women lived longer at each stage

Overall median survival 12.4 mo vs 10.3mo (p<.001) and survival advantage for all stages

RR for MEN= 1.2

*smoking status/dose, comorbidy interaction with cause of death, not significant

nsclc completely resected diseases28
NSCLC: completely resected diseases

EVEN CONSIDERING OTHER DEATH CAUSES

2.1

Bouchardy, et al. Cancer, 1999

alpi multivariate analysis
ALPI Multivariate Analysis

Similar Data from UFT, Kato et al.

Scagliotti GVS, JNCI 2003

nsclc advanced disease
NSCLC: advanced disease*

Favourable factors in

Group N Stage multivariate analysis

MemorialR 378 IIIB/IV Women, normal LDH ,

(O’Connell et al) good PS, no bone mts,

≤ 2 sites mts

ECOGR 893 IV Women, PS 0, no bone mts,

(Finkelstein et al) no liver mts, 7 trials no weight loss,

non-large cell istol.

SWOGR 2,290 IV Women, PS 0-1,

(Albain et al) “cisplatin-based” therapy,

13 trials age ≤70 yrs

Women is a strong indipendent factor for improved survival

*first and second generation chemotherapy

ecog 1594
ECOG 1594

HA Wakelee JTO 2006

patient outcomes for ecog 1594
Patient outcomes for ECOG 1594

- Separately for each arm, trend for improved survival mantained; statistical significance was LOST

HA Wakelee JTO 2006

bevacizumab in advanced nsclc efficacy by gender
Bevacizumab in Advanced NSCLC: Efficacy by Gender

*Statistically significant

  • No survival benefit for females despite 4-fold increase in RR and statistically significant difference for PFS
  • A number of potential explanations (eg, statistical chance, imbalance of unmeasured prognostic factors, or a true difference)

Brahmer et al. J Clin Oncol. 2006;24(No 18S):373s. Abstract 7036.

vandetanib zd6474 with carboplatin and paclitaxel as first line nsclc therapy schema
Vandetanib (ZD6474) With Carboplatin and Paclitaxel as First-Line NSCLC Therapy: Schema

Run-In Phase

Randomized Phase

Vandetanib 200 mg

Paclitaxel 200 mg/m2

Carboplatin AUC 6 mg/mL·min

(n=15)

Vandetanib 300 mg

(n=73) [discontinued]

Vandetanib 300 mg

Paclitaxel 200 mg/m2

Carboplatin AUC 6 mg/mL·min

(n=56)

First-Line NSCLC

First-Line NSCLC

Vandetanib 300 mg

Paclitaxel 200 mg/m2

Carboplatin AUC 6 mg/mL·min

(n=10)

Placebo

Paclitaxel 200 mg/m2

Carboplatin AUC 6 mg/mL·min

(n=52)

Objectives:

Appropriate Dose in Combination Therapy,

Pharmacokinetics, Survival

Heymach et al., IASLC 2005, Abstract P-497

Heymach et al., ASCO 2007, Abstract 7544

vandetanib with carboplatin and paclitaxel cp as first line nsclc therapy efficacy
Vandetanib With Carboplatin and Paclitaxel (CP) as First-Line NSCLC Therapy: Efficacy

No significant differences in PFS or OS based on histology were observed.

*Met prespecified significance level of P < .2

Heymach et al., ASCO 2007, Abstract 7544

slide40

ZD6474 plus docetaxel vs docetaxel in previously treated NSCLC

A randomized, double-blind, two-part, multicenter study

Run-in phase

Randomized phase*

ZD6474 100 mg

Docetaxel 75 mg/m2

n=42

ZD6474 100 mg

Docetaxel 75 mg/m2

n=4

ZD6474 300 mg

Docetaxel 75 mg/m2

n=44

2nd-line NSCLC

2nd-line NSCLC

ZD6474 300 mg

Docetaxel 75 mg/m2

n=11

Placebo

Docetaxel 75 mg/m2

n=41

JV Heymach, ASCO 2006

males vs females exploratory analysis

ZD6474 100 mg + doc (n=42) vs placebo + doc (n=41)

ZD6474 100 mg + doc (n=42) vs placebo + doc (n=41)

Males

ZD6474 300 mg + doc (n=44) vs placebo + doc (n=41)

ZD6474 300 mg + doc (n=44) vs placebo + doc (n=41)

Females

0.25 0.5 1.0 2.0 4.0

Time to progression

All patients

Time to death

Males vs females: exploratory analysis

Hazard ratios and 95% confidence intervals

0.25 0.5 1.0 2.0 4.0

JV Heymach, ASCO 2006

slide42

EGFR Tyrosine Kinase Inhibitors Second and Third Line Therapy

  • Work better in women than men
  • Gefitinib and erlotinib studies: females  RR, more symptom improvement, longer OS (univariate), but no difference in benefit phase III study erlotinib
  • Biologic basis for difference by sex complex: interactions with frequency of activating mutations, EGFR+ (by IHC/amplification), adenocarcinoma or BAC histology, non-smoking status
egfr tyrosine kinase inhibitors
EGFR Tyrosine Kinase Inhibitors
  • Female sex is predictive of response:

- Symptoms improvement: 50% vs 31% (p 0.006)

- Radiographic regression: 19% vs 3% (p=0.001) with 82% of responses among women

Kris MG, JAMA 2003

br 21 trial overall survival by gender
BR.21 Trial: Overall Survival by Gender

_____Erlotinib Female

_____Placebo Female

_____Erlotinib Male

_____Placebo Male

Interaction p = n.s.

Months

Shepherd, NEJM, 2005

slide45

Is there an interaction between the ER and EGFr pathways?

  • EGFR protein expression is down-regulated in response to estrogen
  • EGFR protein expression is up-regulated when estrogen is depleted
  • Suggests “cross-talk” between these two pathways
paclitaxel poliglumex ppx
Paclitaxel Poliglumex (PPX)
  • Macromolecule that combines paclitaxel with poly-L- glutamic acid
  • Into the cell broken in its active form by cathepsin B (regulated by estrogen) minimize systemic exposure & prolong exposure to active drug
slide47

The composite analysis of STELLAR 3 and 4 shows a statistically significant survival benefit for women receiving PPX (p=0.03)

  • The presence of estrogen appear to make PPX a more effective drug
  • PIONEER (Paclitaxel Poliglumex Investigating Outcomes in NSCLC: Establishig Estrogen Response) study is ongoing

Ross H, ASCO 2006

slide48

SCLC: limited disease

Favourable factors in

Group N Multivariate analysis

Danish 443 Cox: women, good PS,

(Osterlind et al) normal sodium e uric acid

CALGB R 1745 Cox: women, good PS,

(Spiegelman et al) age <60 yrs

SWOG R 1,316 Cox: women, PS 0-1, caucasian,

(Albain et al) conc. CT/RT, LDH

1,137 RPA: women, LDH nn,

no pleural effusion,age<70 yrs

slide49

Small Cell Lung Cancer Survival by Sex: retrospective review (4 trials)

Singh, S. et al. J Clin Oncol; 23:850-856 2005

sclc toxicity and outcomes by sex
SCLC: Toxicity and outcomes by sex

1006 Patients (648 m, 358 f)

on 4 trials of similar chemotherapy

  • No difference in treatment delivered or toxic deaths, but greater treatment delays in females, with more toxicity (anemia, neutropenia, stomatitis, emesis)
  • Greater toxicity females significant in multivariate model
  • Females RR higher and overall survival (p<.0001)

Singh, S. et al. J Clin Oncol; 23:850-856 2005

conclusion
Conclusion
  • A better understating of the genetic, metabolic, and hormonal factors in women represents a research priority
  • 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 stage
  • Sex as stratification factor in prospective clinical trials