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Studies in NSCLC Based on Gender and Smoking Differences: Rationale and Outcomes Silvia Novello University of Turin Th

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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Studies in NSCLC Based on Gender and Smoking Differences: Rationale and Outcomes Silvia Novello University of Turin Th

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  1. 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

  2. 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

  3. 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

  4. 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

  5. Meta-Analysis of 28 Lung Cancer Studies* Relative Risk Ratios for Ever Smokers Relative Risk Ratio Histology * 27 case-control Khuder, Lung Cancer, 2001

  6. 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

  7. 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

  8. Some Suggested Explanations • DNA repair capacity • Gender differences in metabolism of carcinogens • Differences in proliferation/growth stimulation (GRPR) • Hormonal interactions

  9. DNA Repair Capacity Host Cell Reactivation Assay + .Acetyl CoA + Chloramphenicol + .Acetyl CoA + Chloramphenicol Acetyl -Chloramphenicol Benzo[a]pyrene Test Lymphocytes

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. Differences in proliferation/growth stimulationEGFR ASCO 2004

  17. 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

  18. 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

  19. 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

  20. 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

  21. 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

  22. Hormone Replacement Therapy and Lung Cancer Risk Some positive • All studies derived from secondary data or exploratory analysis

  23. Hormone Replacement Therapy and Lung Cancer Risk Some show no increase in risk All studies derived from secondary data or exploratory analysis

  24. 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

  25. 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

  26. NSCLC: completely resected diseases

  27. NSCLC: completely resected diseases EVEN CONSIDERING OTHER DEATH CAUSES 2.1 Bouchardy, et al. Cancer, 1999

  28. ALPI Multivariate Analysis Similar Data from UFT, Kato et al. Scagliotti GVS, JNCI 2003

  29. NSCLC: locally advanced disease

  30. 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

  31. ECOG 1594 HA Wakelee JTO 2006

  32. Patient outcomes for ECOG 1594 - Separately for each arm, trend for improved survival mantained; statistical significance was LOST HA Wakelee JTO 2006

  33. Toxicity all grade in ECOG 1594 HA Wakelee JTO 2006

  34. 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.

  35. Survival by Treatment - Males J Brahmer ASCO 2006

  36. Survival by Treatment - Females J Brahmer ASCO 2006

  37. 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

  38. 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

  39. 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

  40. 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

  41. 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

  42. 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

  43. BR.21 Trial: Overall Survival by Gender _____Erlotinib Female _____Placebo Female _____Erlotinib Male _____Placebo Male Interaction p = n.s. Months Shepherd, NEJM, 2005

  44. 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

  45. 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

  46. 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

  47. 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

  48. Small Cell Lung Cancer Survival by Sex: retrospective review (4 trials) Singh, S. et al. J Clin Oncol; 23:850-856 2005

  49. 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

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