Les cancers bronchiques chez la femme: une épidémie? Professeur Jean Trédaniel Unité de cancérologie thoracique Hôpital Saint-Louis

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1 Les cancers bronchiques chez la femme: une épidémie? Professeur Jean Trédaniel Unité de cancérologie thoracique Hôpital Saint-Louis

2 Annual Age-adjusted Cancer Incidence Rates Among Males and Females for Selected Cancers, US, 1975 to CA Cancer J Clin 2007; 57:43-66

3 Annual Age-adjusted Cancer Death Rates Among Females for Selected Cancers, US, 1930 to CA Cancer J Clin 2007; 57:43-66

4 CA Cancer J Clin 2007; 57:43-66

5 Trends in age-standardised (per , world population) mortality rates for cancers by sex in the 25 countries (except Cyprus) of the European Union, Ann Oncol 2007; 18: 593-5

6 Évolution de la mortalité pour les principales localisations de cancer, France, Hill C, Doyon F. Bull Cancer 2007; 94: 7-13

7 Evolution of incidence ( ) and mortality ( ) by cancer, France. Most frequent cancers - Females Rapport IARC, 2007

8 Évolution de la mortalité par cancer du poumon entre 35 et 44 ans. Hill C. Bull Cancer 2004;91:9-14.

9 «Le tabac en France, les vrais chiffres»

10 «Le tabac en France, les vrais chiffres»

11 Cancer du poumon en France en 2002/2003: sexe ratio 84 % 80 % INCIDENCE 2002 MORTALITÉ 2003 (27500 cas) (26214 décès) Hill C, Doyon F. Bull Cancer 2006;93:7-11 Hill C, Doyon F. Bull Cancer 2007; 94: 7-13

12 National survey of non-small cell lung cancer in the United States National Cancer Database: patient care evaluation study in 719 hospitals. Information was obtained on patients Lung Cancer 2007; 57:

13 Lung Cancer in Women. Analysis of the National SEER Database, Chest 2005; 127:

14 Part relative des cancers du poumon parmi les autres cancers chez la femme, France, 2002/2003 4% 9% Autres Poumon Autres Poumon INCIDENCE / MORTALITÉ /59000 Hill C, Doyon F. Bull Cancer 2006;93:7-11 Hill C, Doyon F. Bull Cancer 2007; 94: 7-13

15 National survey of non-small cell lung cancer in the United States 50,6% Lung Cancer 2007; 57:

16 National survey of non-small cell lung cancer in the United States Lung Cancer 2007; 57:

17 Proportion of patients diagnosed with either SQC or ADC by sex Lung Cancer 2007; 55: 15-23

18 Differences in smoking status and histology by sex 90 Women (%) Men (%) Women (%) Men (%) Never-smokers Adenocarcinoma Série 1 Série 2 Série 3 Série 4 Série 5 ASCO educational book, 2007

19 Changing Epidemiology of Small-Cell Lung Cancer in the United States Over the Last 30 Years: Analysis of the Surveillance, Epidemiologic, and End Results Database J Clin Oncol 2006; 24:

20 Proportion of patients diagnosed with lung cancer by sex, histological subtype, and smoking status - Women Lung Cancer 2007; 55: 15-23

21 Chest 2005;128;

22 Lung cancer incidence rates (with 95% confidence bands) by age and sex, generated from a unified model of former and current smokers in the Nurses Health Study of women and the Health Professionals Follow-up Study of men, A ) Lung cancer incidence rates for current smokers who started smoking between ages 15 and 19 years and who currently smoke cigarettes per day. B) Lung cancer incidence rates for former smokers who started smoking between ages 15 and 19 years, quit 10 or more years ago, and smoked cigarettes per day before quitting. JNCI 2004; 96:

23 Lung cancer rates in men and women with comparable histories of smoking JNCI 2004; 96:

24 JNCI 2004; 96:

25 The Association of Human Papillomavirus 16/18 Infection with Lung Cancer among Nonsmoking Taiwanese Women % Lung tumors (%) Normal lung (%) HPV positivity Lung cancer is the leading cause of cancer death in Taiwanese women since High lung cancer mortality ratio of male:female in Taiwan (2:1) was observed, although less than 10% of female lung cancer patients are smokers In this study, 141 lung cancer patients and 60 noncancer control subjects were enrolled to examine whether HPV 16/18 DNA existed in lung tumor and normal tissues by nested PCR and in situ hybridization (ISH), respectively 77 (54.6%) of 141 lung tumors had HPV 16/18 DNA compared with 16 (26.7%; p = ) of 60 noncancer control subjects ISH data showed that HPV 16/18 DNA was uniformly located in lung tumor cells, but not in the adjacent nontumor cells Cancer Res 2001; 61:

26 Human papillomavirus infection is not associated with bronchial carcinoma. % Lung cancer (%) Cervical cancer (%) An analysis of paraffin-embedded tissue from 32 squamous bronchial carcinomas and 15 cervical cancers utilizing both in situ hybridization and PCR techniques was negative for HPV in the lung cancer cases, while 12 of the 15 cervical cases were positive CC: it is possible that an association of HPV in lung cancer reflects the coexistence of increased and earlier smoking behavior with more frequent sexual contacts. HPV positivity by in situ hybridization and PCR J Pathol 1997; 181:

27 Sex-specific expression of gastrin-releasing peptide receptor: relationship to smoking history and risk of lung cancer GRPR is a receptor for the hormone GRP, which mediates cell proliferation in the lung Female never-smokers express this gene in their airway epithelial cells at a significantly higher frequency compared with males, perhaps related to the fact that the GRPR gene is located on the X chromosome (and women escape X-inactivation of the gene). J Natl Cancer Inst 2000; 92: 24-33

28 Sex differences in lung CYP1A1 expression and DNA adduct levels among lung cancer patients p = 0,047 p = 0,0004 DNA adducts Adducts / pack year p = 0,015 Adducts / cigarette / day Males Females Cancer Res 1999; 59:

29 Sex differences in lung CYP1A1 expression and DNA adduct levels among lung cancer patients. Cancer Res 1999; 59:

30 p53 mutations in lung tumours: relationship to gender and lung DNA adduct levels Carcinogenesis 1996; 17:

31 Implications and prognostic value of K-ras mutation for early-stage lung cancer in women. Consecutive, newly diagnosed patients with lung cancer treated with potentially curative resection over a 4-year period were recruited for study. The mutation status of K-ras codon 12 in each patient's tumor DNA was determined by means of PCR-RFLP analysis of archived pathology specimens. Analyses were restricted to adenocarcinoma. RESULTS: There was a statistically significant association between female sex and K-ras mutation after adjustment for carcinogen exposures (odds ratio = 3.3; 95% confidence interval [CI] = ); mutations were found only in smokers. CONCLUSION: After adjustment for environmental exposures, nonsmall-cell lung tumors in women appear to be more likely than those in men to harbor K-ras mutations, suggesting a possible role of estrogen exposure in either the initiation or the selection of K-ras mutant clones in adenocarcinoma J Natl Cancer Inst 1999; 91:

32 Repair of tobacco carcinogen-induced DNA adducts and lung cancer risk: a molecular epidemiologic study DNA repair capacity p < 0,001 p < 0, Case patients Control subjects 2 0 Male Female J Natl Cancer Inst 2000; 92:

33 Repair of tobacco carcinogen-induced DNA adducts and lung cancer risk: a molecular epidemiologic study J Natl Cancer Inst 2000; 92:

34 Perhaps differences in DNA-repair capacity may not only make women more susceptible to lung cancerinducing carcinogens but also more responsive to platinum-based chemotherapy?

35 Hormone differences The primary receptor found in lung tumors is the ER-ß There is documented ER-ß expression in the majority of NSCLC ER-ß activation leads to cell proliferation of lung tumors cells in cell culture There is no sex difference in the extent of ER-ß positivity in lung tumors ER could be targeted therapeutically in lung tumors that express it? ASCO educational book, 2007

36 Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women's Health Initiative Randomized Controlled Trial Lung cancer incidence was not affected : 54 vs 50; HR, 1.04; 95% CI, JAMA 2002; 288:

37 Hormone Replacement Therapy and Lung Cancer Risk. A Case-Control Analysis self-reported HRT use was compared among 499 women with lung cancer and 519 healthy age-matched controls HRT use was associated with an overall reduced risk of 34% [OR = 0.66; 95%CI: ] of lung cancer, after adjusting for age, ethnicity, smoking status, education, body mass index, and menopausal status. Clin Cancer Res 2004; 10:

38 High Frequency of Epidermal Growth Factor Receptor Mutations with Complex Patterns in Non Small Cell Lung Cancers Related to Gefitinib Responsiveness in Taiwan 101 non small cell lung cancer tumor specimens (69 adenocarcinomas) Mutation(s) in the kinase domain (exon 18 to exon 21) of the EGFR gene were identified in 39 patients. All of the mutations occurred in adenocarcinoma The mutation rate in male patients with adenocarcinoma was 54.5% (18 of 33) and 55.5% (20 of 36) in female patients Clin Cancer Res 2004; 10:

39 Erlotinib in Lung Cancer Molecular and Clinical Predictors of Outcome BR-21 trial Mutations were found in 24 percent of specimens from women, 22 percent of specimens from men N Engl J Med 2005; 353:

40 Response to therapy Women Men TAX326-1 TAX TAX326-3 E1594 E E JBR-21 pl JBR-21 erlo ASCO educational book, 2007

41 Lung Cancer in Women. Analysis of the National SEER Database, Chest 2005; 127:

42 Belani et al. Lung Cancer 2007; 55: 15-23

43 Belani et al. Lung Cancer 2007; 55: 15-23

44 Paclitaxel Carboplatin Alone or with Bevacizumab for Non Small-Cell Lung Cancer N Engl J Med 2006; 355:

45 CONCLUSION The importance of stratification by sex in future trials is evident