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![Page 1: Studies in NSCLC Based on Gender and Smoking Differences: Rationale and Outcomes Silvia Novello University of Turin Thoracic Oncology Unit .](https://reader030.fdocuments.net/reader030/viewer/2022032522/56649d695503460f94a47adc/html5/thumbnails/1.jpg)
Studies in NSCLC Based on Gender and Smoking
Differences: Rationale and Outcomes
Silvia Novello University of Turin Thoracic Oncology Unit
www.oncologiapolmonare.it [email protected]
www.womenagainstlungcancer.eusilvia.novello@[email protected]
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Males
Rat
e p
er 1
00,0
00 M
ales
Year of Death
Rat
e p
er 1
00,0
00 F
emal
es
Year of Death1930 1950 1970 1990
Lung & BronchusStomachColon & RectumProstateLiver
1930 1950 1970 1990 2004
LeukemiaPancreas
Females
Annual Age-Adjusted Cancer Death Rates Among Males/Females
for Selected Cancer Types, US, 1930-2004
Colon & RectumStomachOvaryUterusBreastLung & BronchusPancreas
CA Cancer J Clin 2004; 54:9-15
20040
20
40
60
80
100
0
20
40
60
80
100
Lung & Bronchus
Lung & Bronchus
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Lopez et al, Tobacco Control 1994
Smoke kills about 50% of smokers: there are 3-4 Smoke kills about 50% of smokers: there are 3-4 decades between prevalence peak and mortality decades between prevalence peak and mortality peak for lung cancerpeak for lung cancer
Model of Smoking Epidemic
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Lifetime Probability of Developing Cancer
1997-2001
All sites 1 in 3
Breast 1 in 7
Lung & bronchus 1 in 18
All sites 1 in 2
Prostate 1 in 6
Lung & bronchus1 in 13
Site Risk Site Risk
ACS, 2005
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11,3
14,6
9,9
25,5
3,9 3,4
6,78,1
0
10
20
30
Squamouscell
SCLC Adeno-carcinoma
Large cell
Men
Women
Rela
tive R
isk R
ati
oR
ela
tive R
isk R
ati
o
HistologyHistology
Khuder, Lung Cancer, 2001
Meta-Analysis of 28 Lung Cancer Studies*
Relative Risk Ratios for Ever Smokers
Meta-Analysis of 28 Lung Cancer Studies*
Relative Risk Ratios for Ever Smokers
* 27 case-control
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Women and Lung Cancer Risk (smokers vs non-smokers)
Author Study Men Women n.cigarettesRisch case- 9.6 27.9 40 packs/yrAm J Epidemiol ’93 control
Zhang case- 11.6 21.4 40 packs/yrJ Natl Cancer Inst ’96 control
Harris case- 24.5 42 40 packs/yrInt J Epidemiol ’93 control
Bach cohort no differenceJ Natl Cancer Inst ’03
Bain cohort no difference J Natl Cancer Inst ‘04
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• 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
• 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
• 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
• In some Asian countries never-smokers account for 70% of women with lung cancer Wong MP et al: Cancer 2003
Women and Lung Cancer
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• DNA repair capacity
• Gender differences in metabolism of carcinogens
• Differences in proliferation/growth stimulation (GRPR)
• Hormonal interactions
• DNA repair capacity
• Gender differences in metabolism of carcinogens
• Differences in proliferation/growth stimulation (GRPR)
• Hormonal interactions
Some Suggested ExplanationsSome Suggested Explanations
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DNA Repair Capacity
Host Cell Reactivation Assay
Benzo[a]pyrene
TestLymphocytes
Acetyl -Chloramphenicol
+ .Acetyl CoA
+ Chloramphenicol
+ .Acetyl CoA
+ Chloramphenicol
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DRC and Risk of Lung Cancer
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)
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)
Variable Adjusted OR(95% CI) Variable Adjusted OR(95% CI)
Spitz et al, CEBP, 2003
n = 764 cases and 677 controls
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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
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
Variable No Mean % p-valueSD for trend
Variable No Mean % p-valueSD for trend
DNA Repair CapacityLung Cancer Cases
Spitz, CEBP, 2003
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Age (yrs)
< 60 109 100.8 ± 94.6 0.05
61+ 112 85.8 ± 83.6
Gender
Male 114 100.1 ± 89.1 NSFemale 107 85.8 ± 89.4
Smoking status Never 21 103.7 ±101.6 NS Former 8587.1 ± 75.0 Current 11595.8 ± 97.0
Age (yrs)
< 60 109 100.8 ± 94.6 0.05
61+ 112 85.8 ± 83.6
Gender
Male 114 100.1 ± 89.1 NSFemale 107 85.8 ± 89.4
Smoking status Never 21 103.7 ±101.6 NS Former 8587.1 ± 75.0 Current 11595.8 ± 97.0
Variable N Mean(%)SD P valueVariable N Mean(%)SD P value
Induced Adduct LevelsLung Cancer Cases
Li et al, Cancer Res 2001Li et al, Cancer Res 2001
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Gender differences in metabolism of carcinogens
CYP1A1• 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
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Gender differences in metabolism of carcinogens
Glutathione S-transferase (GST)
Odds ratio for GSTM1 null phenotype and WT
Female (CI)
Male (CI)
Lung cancer2.50
(1.09-5.72)1.40
(0.58 - 3.38)
Lung cancer in smokers
3.03 (1.09 -8.40)
1.42 (.053-4.06)
•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
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• Gastrin-Releasing Peptide (GRP): plays a role in neoplasia by stimulating cell proliferation. Its effect is mediated mainlythrough 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.
Differences in proliferation/growth stimulationGRP
Shriver SP 2000, JNCI
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Differences in proliferation/growth stimulation
EGFR
CharacteristicsPatients with
mutation/total
In unselected pts
Adenocarcinoma
14/182 (8%)
15/152 (10%)
Women with adenocarcinoma
12/83 (15%)
Women non-smokers with adenocarcinoma
18/34 (53%)
ASCO 2004
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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
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β-estradiol inducesproliferation in NSCLC cells and anti-estrogens block this effect
Kiuper, 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
Hormonal Interactions
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Cross-Talk Cascade of ER Activation IGFR
PlasmaMembrane
Cytoplasm
Akt
SOS
P
P
P
P
MAPK
MEK
Nucleus
p90RSK
p160ERER CBP
BasalTranscription
Machinery
ERE
P P P
ER Target Gene Transcription
P
P
P
P
RAS
RAFPI3-K
PP
P
Growth factors
Estrogen
ER
EGFR / HER2
AI
MoAb
TKI
FTI
CCI
CellGrowth
Cell Survival
Tamoxifen
SERD
Johnston, S. 2004
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Decreased Cell Proliferation in Lung Tumors Treated with Gefitinib and
Fulvestrant
Rela
tive K
i67 E
xp
ressio
n
0
20
Treatments
control fulvestrant fulvestrant +gefitinib
gefitinib
40
60
80
100
120
*
**
**
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 + 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
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Hormone Replacement Therapy and Lung Cancer Risk
Some positive
Type of Study
NRisk of lung Ca
with HRT95% CI
Taioli, JNCI, 1994
Case control
180 1.7 1.0-2.8
•All studies derived from secondary data or exploratory analysis
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Hormone Replacement Therapy and Lung Cancer Risk
Some show no increase in risk
Type of Study NRisk of lung Ca with
HRT95% CI
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, Pharmacoepidemiol Drug Saf, 2002
Case Control 662 1.0
All studies derived from secondary data or exploratory analysis
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Hormone Replacement Therapy and Lung Cancer Risk
Some show REDUCED risk of lung cancer with HRT
Type of study
NRisk of lung Ca
with HRT95% CI
Ettinger, Ob Gynecol, 1996
454 0.78 0.04-1.15
Krenzer, 1993
Case control
1723 0.83 0.64-1.09
Olson, Ob Gyne, 1993
Cohort 29,508 0.24 0.08-0.76
Schabath, Clin Ca Res, 2004
Case Control
1008 0.66 0.51 - 0.89
All studies derived from secondary data or exploratory analysis
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Sex as a predictive factor
Study N Unfavorable in
Multivariate Analysis
Radzikowska (1995-98) 20,561 Male, poor PS, advancedPolish population, all stage, non surgical
treatment, >50 yrs, SCLC
Ouellete (1988-90) 208 Male, advanced stageFrench population, cohort
Moore (1974-98) 7,613 Male, age >65, advancedSingle 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**smoking status/dose, comorbidy interaction with cause of death, not significant
Relative risk (RR) of death for MEN = 1.15 (p=0.001)
NO differences in overall mean survival
BUT women lived longer at each stageOverall median survival 12.4 mo vs 10.3mo (p<.001) and survival advantage for all stages
RR for MEN= 1.2
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NSCLC: completely resected diseases
NSCLC: completely resected diseases
Author # Women Survival
MinamiR (#1242 consec.1984-1998)
[adavntage also for st I &III,adenoca & > 60yrs]
FergusonR (#451)
1980-1998
AlexiouP (#833)
UK 1990-2000
337
186
252
5yr 69% p<.005
st I OS 109vs50 mo p .008
5yr 48%vs36.5% p<0.01
OS p 0.0006
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NSCLC: completely resected diseases
Bouchardy, et al. Cancer, 1999
EVEN CONSIDERING OTHER DEATH
CAUSES
2.1
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ALPI Multivariate AnalysisALPI Multivariate Analysis
Variable HR 95% CI P Value
Age (5-yr interval)
1.06 1.00-1.12
.051
Stage II III
2.003.15
1.6-2.52.6-3.9
.0001
.0001
Histology-Squamous
0.86 0.7-1.0 .094
Gender – Male(86%)
1.32 1.0-1.7 .034
Complete Dissection
0.89 0.8-1.1 .164
Chemotherapy 0.96 0.8-1.1 .566
Scagliotti GVS, JNCI 2003Similar Data from UFT, Kato et al.
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NSCLC: locally advanced disease
Werner WasikR (RTOG)- #1,999- 9 studies
OS 11.4 vs 9.9 mo
AlbainP (SWOG)- #126- st IIIA, IIIB
OS 21 vs 12 mo (p0.08)
AlbainP (RTOG 93-09)-#429 (35%)- st IIIA
> OS in women(p=0.051)
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NSCLC: advanced disease*
Favourable factors inGroup 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 trialsno 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
male female P Value
MULTIVARIATE
median survival 8.8 mo 12.4 mo 0.001
*first and second generation chemotherapy
male female P ValueMULTIVARIAT
E
1 yr survival rate
16% 26% 0.005
Women is a strong indipendent factor for improved survival
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ECOG 1594
Study # PtsSt. IV,
%ORR,%
MST (mos.)
G4ANC,
%
G4Plts,
%
G> 3Neuro,
%
ECOG 1594DDP-TAXDDP-GEMDDP-TXTCb-TAX
292288293290
9121.32117.3
15.3
8.18.17.48.3
57 394943
22912
59510
HA Wakelee JTO 2006
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Patient outcomes for ECOG 1594
N=1157Women (433)
Men (726) P value
Response rate (%)Median PFS (mo)Median survival time (mo)
193.8
9.2 mo
193.57.3
0.990.0220.004
- Separately for each arm, trend for improved survival mantained; statistical significance was LOST
HA Wakelee JTO 2006
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Toxicity all grade in ECOG 1594
N=1157Women (431)
Men (726)
P value
Nausea (%)Vomiting (%)Alopecia (%)Neurosensory (%)Neuropsychiatric (%)Cardiac Toxicity ≥ g3 (%)
83656449224.1
70525342147.6
<0.0001<0.00010.00030.020.0010.02
HA Wakelee JTO 2006
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Bevacizumab in Advanced NSCLC: Efficacy by Gender
Brahmer et al. J Clin Oncol. 2006;24(No 18S):373s. Abstract 7036.
ParameterMales Females
PC (n=230)
PCB (n=191)
PC(n=162)
PCB(n=190)
OS, mo 8.7 11.7* 13.1 13.3
PFS, mo 4.3 6.3* 5.3 6.2*
RR, % 16 29* 14 41*
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)
*Statistically significant
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Survival by Treatment - Males
0.0
0.2
0.4
0.6
0.8
1.0
Months
Pro
ba
bili
ty
0 6 12 18 24 30 36 42
PC (219 events/ 253 cases)PCB (158 events/ 210 cases)
P = 0.0010
Medians: 8.7, 11.7
J Brahmer ASCO 2006
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Survival by Treatment - Females
J Brahmer ASCO 2006
0.0
0.2
0.4
0.6
0.8
1.0
Months
Pro
ba
bili
ty
0 6 12 18 24 30 36 42
PC (125 events/ 180 cases)PCB (147 events/ 207 cases)
P = 0.87
Medians: 13.1, 13.3
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Vandetanib 200 mgVandetanib 200 mgPaclitaxel 200 mg/mPaclitaxel 200 mg/m22
Carboplatin AUC 6 mg/mL·minCarboplatin AUC 6 mg/mL·min(n=15)(n=15)
Randomized PhaseRun-In Phase
Vandetanib 300 mgVandetanib 300 mgPaclitaxel 200 mg/mPaclitaxel 200 mg/m22
Carboplatin AUC 6 mg/mL·minCarboplatin AUC 6 mg/mL·min(n=10)(n=10)
Vandetanib 300 mgVandetanib 300 mg(n=73) (n=73) [discontinued][discontinued]
Vandetanib 300 mgVandetanib 300 mgPaclitaxel 200 mg/mPaclitaxel 200 mg/m22
Carboplatin AUC 6 mg/mL·minCarboplatin AUC 6 mg/mL·min(n=56)(n=56)
PlaceboPlaceboPaclitaxel 200 mg/mPaclitaxel 200 mg/m22
Carboplatin AUC 6 mg/mL·minCarboplatin AUC 6 mg/mL·min(n=52)(n=52)
Vandetanib (ZD6474) With Carboplatin and Paclitaxel
as First-Line NSCLC Therapy: Schema
Objectives:Objectives:Appropriate Dose in Combination Therapy, Appropriate Dose in Combination Therapy, Pharmacokinetics, SurvivalPharmacokinetics, Survival
Fir
st-L
ine
NS
CL
CF
irst
-Lin
e N
SC
LC
Fir
st-L
ine
NS
CL
CF
irst
-Lin
e N
SC
LC
Heymach et al., IASLC 2005, Abstract P-497Heymach et al., ASCO 2007, Abstract 7544
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Vandetanib With Carboplatin and Paclitaxel (CP) as First-Line NSCLC Therapy: Efficacy
Vandetanib/CP
n = 56
Placebo/CP
n = 52
HR P Value
ORR 32% 25% - -
Median OS 10.2 months 11.9 months 1.07 .595
Median PFS 24.0 weeks 23.1 weeks 0.76 .098*
Exploratory Analysis (females)
n = 17 n = 15
Median PFS 28.6 weeks 11.7 weeks 0.47 .037
Median OS ≥ 8.6 months 5.8 months 0.52 .113
Heymach et al., ASCO 2007, Abstract 7544*Met prespecified significance level of P < .2
No significant differences in PFS or OS based on histology were observed.
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ZD6474 plus docetaxel vs docetaxel in previously treated NSCLC
A randomized, double-blind, two-part, multicenter study
2nd
-lin
e N
SC
LC
ZD6474 100 mgDocetaxel 75 mg/m2
n=4
Randomized phase*Run-in phase
2nd
-lin
e N
SC
LC
ZD6474 100 mgDocetaxel 75 mg/m2
n=42
PlaceboDocetaxel 75 mg/m2
n=41
ZD6474 300 mgDocetaxel 75 mg/m2
n=11
ZD6474 300 mgDocetaxel 75 mg/m2
n=44
JV Heymach, ASCO 2006
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0.25 0.5 1.0 2.0 4.0
Time to progression
Time to death
Males vs females: exploratory analysis
Hazard ratios and 95% confidence intervals
0.25 0.5 1.0 2.0 4.0
Males
Females
All patients
ZD6474 100 mg + doc (n=42) vs placebo + doc (n=41)
ZD6474 300 mg + doc (n=44) vs placebo + doc (n=41)
ZD6474 100 mg + doc (n=42) vs placebo + doc (n=41)
ZD6474 300 mg + doc (n=44) vs placebo + doc (n=41)
JV Heymach, ASCO 2006
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• 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 Second and Third Line Therapy
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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
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BR.21 Trial: Overall Survival by Gender
SUMMARY STATISTICS:Log-Rank test for equality of groups: p=0.0025
Female/OSI-774 Female/PlaceboMale/OSI-774 Male/Placebo
Perc
enta
ge
0
20
40
60
80
100
Time (months) # At Risk(Female/OSI-774) # At Risk(Female/Placebo) # At Risk(Male/OSI-774) # At Risk(Male/Placebo)
0.017383
315160
10.0752711332
20.03292
30.00000
_____ Erlotinib Female
_____ Placebo Female
_____ Erlotinib Male
_____ Placebo Male
Months
Interaction p = n.s.
Shepherd, NEJM, 2005
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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
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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
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ELIGIBILITY CRITERIA
chemonaive
advanced NSCLC
PS2
STRATIFIED BY
disease stage
sex
brain mts
geography
STELLAR 3
PPX 210 mg/mq + CBDCA AUC6 Q3w
versus
Paclitaxel 225 mg/mq + CBDCA AUC 6 Q3w
STELLAR 4
PPX 175 mg/mq Q3w
versus
GMC 1200 mg/mq d1,8,15 Q4w OR NVB 30 mg/mq d 1,8,15 Q3w
Ross H, ASCO 2006
-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
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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
SCLC: limited disease
Albain (10 SWOG trials from 1976 to1988)
male female
MST
LD
ED
17.7mo
no
24.4mo
differences
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Singh, S. et al. J Clin Oncol; 23:850-856 2005
Small Cell Lung Cancer Survival by Sex: retrospective review (4 trials)
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SCLC: Toxicity and outcomes by sex
• 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)
1006 Patients (648 m, 358 f)
on 4 trials of similar chemotherapy
Singh, S. et al. J Clin Oncol; 23:850-856 2005
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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