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Gender Differences in Lung Cancer ( Molecular Biology )

Gender Differences in Lung Cancer ( Molecular Biology ). Silvia Novello University of Turin-Italy silvia.novello@unito.it www.womenagainstlungcancer.eu. Incidence rates from SEER (1975-1999). 9.3% ♂ 40.5% ♀. N=228,572 (35.8% ♀) ♀ = 40.9% of pts younger than 50 yrs at diagnosis

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Gender Differences in Lung Cancer ( Molecular Biology )

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  1. Gender Differences in Lung Cancer (Molecular Biology) Silvia Novello UniversityofTurin-Italy silvia.novello@unito.it www.womenagainstlungcancer.eu

  2. Incidence rates from SEER (1975-1999) 9.3% ♂ 40.5% ♀ • N=228,572 (35.8% ♀) • ♀ = 40.9% of pts younger than 50 yrs at diagnosis • Histologic subtypes differed significantly between ♀ and ♂(p<0.0001) • Incidence rates for SCLC and squamous decreased for ♂ and increased for ♀ Fu JB, Chest 2005

  3. European cancer mortality predictions for the year 2011 Recorded deaths in : *2007; # 2006; § 2008; ^ 2005. • EU data • Men Lung Cancer rate 37.6/100000 (9% lower than the rate recorded in 2007) • Women Lung Cancer Rate 13.1/100000 (8.4 higher) being 15.1 for breast Malvezzi M et al, Ann Oncol 2011

  4. Lung Cancer: Estimated incidence and mortality Women, 2008 Breast Cancer: Estimated incidence and mortality Women, 2008

  5. Italy: smoking habit changes among genders

  6. “Questa non me la fumo” • Big book with tales • 24 notebooks for kids • box game for the class • a teacher’s guide

  7. Potential Increased Risk from Smoking for Women 2.7 SIGNIFICANT INCREASE IN LC RATE FOR W NEVER SMOKERS compared WITH M

  8. Gender-based Differences in NSCLC: baseline characteristics Donington J et al Sem in Thorac and Cardiovasc Surg 2011

  9. Some Suggested Explanations to support Gender Differences • DNA repair capacity • Gender differences in metabolism of carcinogens • Differences in proliferation/growth stimulation (GRPR) • Hormonal interactions Lung Cancer Fourth Edition, Gender-Related Differences in Lung Cancer Novello S, Brahmer JR, Stabile LP, Siegfried JM

  10. Some Suggested Explanations to support Gender Differences • DNA repair capacity • Gender differences in metabolism of carcinogens • Differences in proliferation/growth stimulation (GRPR) • Hormonal interactions Lung Cancer Fourth Edition, Gender-Related Differences in Lung Cancer Novello S, Brahmer JR, Stabile LP, Siegfried JM

  11. Gender-based Differences in NSCLC: molecular target Donington J et al Sem in Thorac and Cardiovasc Surg 2011

  12. Gender Differences in DSB genes To test sex-related differences in the expression of selected genes involved in DNA repair mRNA levels of 22 DNA repair genes were evaluated in 50 consecutive early stage chemo-näive NSCLC patients and in corresponding normal tissue Quantified by Real-Time PCR Novello S et al, JTO 2008

  13. Results • Genes belonging to DSB had a significant sex-specific over-expression rate • 71% of DSB genes (5 out of 7) had significant higher transcript levels in male patients compared to female (p< 0.03) • BRCA1 (p= 0.01), BRCA2 (p= 0.005) and XRCC3 (p= 0.004) were the DSB genes more strongly over-expressed in male patients Novello S et al, JTO 2008

  14. BRCA1 BRCA2 p=0.01 p=0.005 Female Male Female Male XRCC3 p=0.004 Female Male Results Overexpression level Overexpression level Overexpression level Novello S et al, JTO 2008

  15. XRCC4 UBE2V2 p=0.20 Overexpression level Overexpression level Female Male Female Male Results • All the other genes from other pathways were not significantly correlated with gender P=0.24 Novello S et al, JTO 2008

  16. Female Gender as indipendent Prognostic Factor in NSCLC: a Meta-analysis N trials: 39 N pts: 86800 % ♀: 37.7% Nakamura H et al, Ann Thorac Cardiovasc Surg 2011

  17. Gender and EGFR mutations No mutation detected NRAS<1% KRAS (22%) MEK1<1% EGFR (18%) MET AMP<1% EML4-ALK (7%) HER2 1% Double mutants (2%) PIK3CA 1% BRAF (2%) AKT1 Shepherd F et al, NEJM 2005 Johnson , et al. ECCO ESMO 2011. Abstract 9018. Tanaka T et al, Int J Cancer 2010

  18. Gender and EGFR mutations: change in clinical Trials Population IPASS Trial Demographic and baseline characteristics in the ITT population 252M/965F INCLUSION CRITERIA T Mok et al, New England Journal of Medicine, 361: 2009 R Rosell et al, New England Journal of Medicine, 361: 2009

  19. Never Smokers and Passive Smoking: correlation with EGFR mutations Inclusion Criteria -126 pts with NSCLC with a smoking history < 100 cigarettes during lifetime -124 lung cancer pts with a passive smoking history were screened for EGFR and k ras mutational status Biological analyses 1. EGFR mutations were detected in 83 out of 126 pts 2. k-ras mutation was found in 2/98 pts Results Cumulative dose of passive smoking (CDP) and gender were significantly associated with the incidence of EGFR mutations (OR: 2.07 for gender; 95%CI: 1.17 to 3.85; p 0.0145) T Kawaguchi, ASCO 2010

  20. Gender and KRAS Mutation No mutation detected NRAS<1% KRAS (22%) MEK1<1% EGFR (18%) MET AMP<1% EML4-ALK (7%) HER2 1% Double mutants (2%) PIK3CA 1% BRAF (2%) AKT1 KRAS mutation type as a function of smoking history Johnson , et al. ECCO ESMO 2011. Abstract 9018. Riely GJ, Clin Cancer Res 2008 Nelson HH, J Natl Cancer Res 1999

  21. Gender and Alk Translocation No mutation detected NRAS<1% KRAS (22%) MEK1<1% EGFR (18%) MET AMP<1% EML4-ALK (7%) HER2 1% Double mutants (2%) PIK3CA 1% BRAF (2%) AKT1 Johnson D, et al. ECCO ESMO 2011. Abstract 9018. Response by Pts Characteristics 1. Camidge et al., ASCO 2011; Abs #2501 2. Riely et al., IASLC 2011; Abs #O31.05

  22. Gender and Braf mutations No mutation detected NRAS<1% KRAS (22%) MEK1<1% EGFR (18%) MET AMP<1% EML4-ALK (7%) HER2 1% Double mutants (2%) PIK3CA 1% BRAF (2%) Johnson D, et al. ECCO ESMO 2011. Abstract 9018. AKT1 ADENOCARCINOMA MELANOMA Paik PK et al, JCO 2011 Marchetti A et al, JCO 2011

  23. Some Suggested Explanations to support Gender Differences • DNA repair capacity • Gender differences in metabolism of carcinogens • Differences in proliferation/growth stimulation (GRPR) • Hormonal interactions Lung Cancer Fourth Edition, Gender-Related Differences in Lung Cancer Novello S, Brahmer JR, Stabile LP, Siegfried JM

  24. Hormonal Interactions β-estradiolinduces proliferation in NSCLC cells and anti-estrogens block thiseffectKiuper, Endocrinology 1997 • Oestrogensmaybeinvolved in lungtumorigenesis at differentlevels: • As ER ligandsactivatingcellproliferation • Via ERs in the plasma membrane causinginteractionsbetweenERs and • growthfactorssuchas EGF and IGF (in EGFR and ER+cells) • Oestrogensmay alter metabolicactivationofcarcinogens (modulations • of CY1A1, CY1B1) Stabile L; CancerRes 2005

  25. Studies on ERs in Neoplastic Lung Disease M.K. Verma et al., Journal of Steroid Biochemistry & Molecular Biology 127 (2011) 216– 222

  26. Hormone Replacement Therapy (HRT) and Lung Cancer Risk =

  27. HRT and Survival in ♀ with Lung Cancer • N= 498 ♀: HRT 17%, smokers 86%, NSCLC 76% • OS is longer in pts who had never used HRT (79 v 39 • months, respectively; HR1.97; 95% CI, 1.14 to 3.39) • This effect seemed to be more pronounced in women with a smoking history Ganti AK et al, JCO 2006

  28. Estrogen: Therapeutic Implications Bouchardy C et al , Cancer 2011

  29. 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

  30. 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, Lung Cancer 2009

  31. OngoingTrials • Phase II trial evaluatingadditionofFulvestranttoerlotinib in patientswith stage IIIb/IV non-smallcelllungcancer (NSCLC) who are stable on erlotinib and exhibit IHC or PCR positivityforestrogen or progesterone receptor . • Bazhenova L, et al. Abstr TPS292 • Randomizedphase II erlotinib alone or in combinationwithFulvestrant in previouslytreatedpatientswithadvancednon-smallcelllungcancer. • Garon EB, et al. Abstr TPS293 • Fulvestrant and Anastrozole as Consolidation Therapy in Postmenopausal Women With Advanced Non-small Cell Lung Cancer PI AhmadTarhini; NCT00932152 UW/UPitt Pilot Study of Gefitinib + Faslodex 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

  32. Combined analysis of estrogen receptor β and progesterone receptor expression identifies lung cancer pts with poor outcome • N= 183 (Female 50%) • Age: 38-92 (median 68) • 56% Adenocarcinoma • Tissues include primary Tumors and (when possible) non-neoplastic lung • IHC and RT-PCR evaluation • Expression significantly higher in lung tumor compared to normal tissue for Erα cyto, Erβ cyto and nuclear • Expression significantly higher in normal lung compared to cancer tissue for nuclear PR • Women had significantly better OS compared to men Stabile L et al, CCR Nov 2010

  33. Combined analysis of estrogen receptor β and progesterone receptor expression identifies lung cancer pts with poor outcome Prognostic Significance of PR and Erβ cyto considered toghether : 1.48 vs 2.94 yrs Stabile L et al, CCR Nov 2010

  34. Combined analysis of estrogen receptor β and progesterone receptor expression identifies lung cancer pts with poor outcome TTP was significantly longer in pts with high versus low PR (1.93 yrs vs 1.03 yrs; p=0.038) Stabile L et al, CCR Nov 2010

  35. Combined analysis of estrogen receptor β and progesterone receptor expression identifies lung cancer pts with poor outcome High ERβ cyto, high EGFR and low PR total : shorter OS (median OS=1.66 years; p=0.026) and TTP (median TTP= 0.76 years; p=0.004) than those with the opposite (n = 44, median OS= 3.50 years, median TTP= 2.75 years) Stabile L et al, CCR Nov 2010

  36. Aromatase in LungCancer Lower levels of aromatase predicted a greater chance of survival in women 65 years and older with diagnosis of lung cancer. Mah V, Cancer Res 2007

  37. www.womenagainstlungcancer.eu

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