SEARCH

SEARCH BY CITATION

Keywords:

  • lung cancer;
  • breast cancer;
  • mortality risk;
  • anti-estrogens;
  • epidemiology;
  • population-based study

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

BACKGROUND:

The Women's Health Initiative randomized clinical trial reported that menopausal hormone therapy increases lung cancer mortality risk. If this is true, use of anti-estrogens should be associated with decreased lung cancer mortality risk. The authors compared lung cancer incidence and mortality among breast cancer patients with and without anti-estrogen therapy.

METHODS:

Our study included all 6655 women diagnosed with breast cancer between 1980 and 2003 and registered at the Geneva Cancer Registry. Among these women, 46% (3066) received anti-estrogens. All women were followed for occurrence and death from lung cancer until December 2007. The authors compared incidence and mortality rates among patients with and without anti-estrogens with those expected in the general population by Standardized Incidence Ratios (SIRs) and Standardized Mortality Ratios (SMRs).

RESULTS:

After a total of 57,257 person-years, 40 women developed lung cancer. SIRs for lung cancer were not significantly decreased among breast cancer patients with and without anti-estrogens (0.63, 95% confidence intervals [CI], 0.33-1.10; and 1.12, 95% CI, 0.74-1.62, respectively) while SMR was decreased among women with anti-estrogens (0.13, 95% CI, 0.02-0.47, P<.001) but not for women without anti-estrogens (0.76, 95% CI, 0.43-1.23).

CONCLUSIONS:

Compared with expected outcomes in the general population, breast cancer patients receiving anti-estrogen treatment for breast cancer had lower lung cancer mortality. This study further supports the hypothesis that estrogen therapy modifies lung cancer prognosis. Cancer 2011. © 2011 American Cancer Society.

The incidence of lung cancer has increased strongly among women in Switzerland and other industrialized countries because of the smoking epidemic among young women.1 Despite treatment progress, survival remains poor with only <16% of patients surviving more than 5 years after diagnosis.2 Although smoking is the main cause for lung cancer occurrence, other factors may act as modulators of the risk or the natural history of the disease. In particular, hormonal factors that play an important role in lung development, and maturation could also be involved in lung carcinogenesis. There is biological evidence that some lung cancer cells express active hormone receptors,3, 4 and experimental studies report growing evidence that estrogens may promote lung tumor occurrence and progression.5–8 However, studies evaluating the association between menopausal hormone use containing estrogen alone, or combined estrogen and progestin and lung cancer incidence9–20 or mortality,16, 20–25 provide conflicting results. Results from randomized controlled trials showed similar risk of lung cancer incidence13, 20 but reported an increased risk of lung cancer mortality among women with versus without hormone replacement therapy (HRT).20 In particular, the Women's Health Initiative randomized clinical trial reported a 60% (hazard ratio [HR], 1.59, 95% confidence interval [CI], 1.03-2.46) increased risk of dying from nonsmall cell lung carcinoma (NSCLC) among women in the hormone therapy arm versus women in the placebo arm.20

If exposure to estrogen increases a woman's risk of dying as a result of lung cancer, then anti-estrogens may, on the contrary, potentially reduce this risk. Women with breast cancer offer a unique possibility to examine the role of anti-estrogens on lung cancer incidence and mortality because many of these women will receive anti-estrogens (tamoxifen or aromatase inhibitors) as part of their multimodality treatment. In this population-based study, we evaluated lung cancer incidence and mortality risk among breast cancer patients with and without anti-estrogen therapy.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Study Population

We used information from the population-based Geneva Cancer Registry, which records all incident cancer cases occurring in the population of the canton of Geneva (approximately 440,000 inhabitants) since 1970. The Cancer Registry extracts information from various sources and is considered accurate; it has a very low percentage (<2%) of cases recorded from death certificates only.1 All hospitals, pathology laboratories, and private practitioners in the canton are requested to report every cancer case. Trained tumor registrars systematically extract data from medical and laboratory records. Physicians regularly receive inquiry forms to complete missing clinical and therapeutic data.

Recorded data include sociodemographic information, method of detection, type of confirmation, tumor characteristics (coded according to the International Classification of Diseases for Oncology, ICD-O),26 hormone receptor status, stage of disease at diagnosis, treatment during the first 6 months after diagnosis, survival status, and cause of death.27

The Cancer Registry regularly assesses survival. The index date refers to the date of confirmation of diagnosis or the date of hospitalization when it preceded the diagnosis and was related to the disease. In addition to passive follow-up (routine examination of death certificates and hospital records), active follow-up is performed yearly using the files of the Cantonal Population Office in charge of the registration of the resident population. Cause of death is systematically recorded and validated by consulting medical files or, when necessary, by sending a specific questionnaire to the patient's physician. Cause of death is coded according to the International Statistical Classification of Diseases and Related Health Problems (ICD-10).27

In the current study, we included all patients diagnosed with invasive breast cancer between 1980 and 2003. We excluded breast cancer cases diagnosed at death (n = 60). The final cohort consisted of 6655 breast cancer patients.

Because of differences in data availability, we separated the period of diagnosis 1980-1990, when information was less exhaustive, from the period 1991-2003. Socioeconomic status was regrouped in 3 levels: low (manual employees, skilled and unskilled workers, including farmers), middle (nonmanual employees and administrative staff), and high (professionals, executives, administrators, entrepreneurs) based on the patient's last occupation or, if unemployed, that of the spouse. Familial risk was categorized as high (at least 1 first-degree relative with breast or ovarian cancer diagnosed before the age of 50 years), low (no affected first- or second-degree relatives with breast or ovarian cancer), or moderate (all other known family histories). Staging was based on the pathologic tumor-node-metastasis (TNM) classification or, when absent, the clinical TMN classification.28

Method of discovery was considered as consultation following symptoms, mammography or clinical screening, and other. Breast cancer histology was classified as ductal carcinoma, lobular carcinoma, other, and unknown (no microscopic confirmation). Hormone receptor status was classified as positive (≥10% of tumor cells expressing receptors) or negative (<10% tumor cells expressing receptors). Treatment was classified as surgery (breast-conserving surgery, mastectomy), radiotherapy (yes, no), chemotherapy (yes, no), and anti-estrogen therapy (yes, no). During the study period anti-estrogen therapy consisted mainly of tamoxifen because aromatase inhibitors were prescribed in Switzerland only from 2006.

As information on smoking exposure is not routinely recorded in the cancer registry database, we retrospectively extracted this data from medical files. Women were classified as never or ever smokers and within the latter group as former smokers (defined as individuals who stopped smoking at least 1 year before the breast cancer diagnosis) or current smokers (defined as individuals who smoked at the time of breast cancer diagnosis). Tobacco consumption was expressed as number of pack-years smoked (calculated by multiplying the number of packs of cigarettes smoked per day by the number of years the person has smoked).

Statistical Methods

We compared patient and tumor characteristics among women with versus without tamoxifen by chi-square test of heterogeneity.

Patients were followed for lung cancer incidence and mortality from 6 months after the date of breast cancer diagnosis until December 31, 2007. Person-years at risk were calculated to the date of end of follow-up, date of departure from the canton, date of lung cancer diagnosis, or date of death, whichever came first.

Expected numbers of lung cancer cases and lung cancer deaths were calculated on the basis of the cantonal lung cancer incidence and mortality rates for each 5-year age group and calendar year. Standardized Incidence Ratios (SIRs) and Standardized Mortality Ratios (SMRs) were then calculated by dividing the observed numbers by the expected numbers. Statistical significance and 95% confidence intervals were estimated assuming a Poisson distribution.

We also modeled SIRs and SMRs by fitting Poisson regression models using the natural logarithm as a link and including the natural logarithm of the expected number of events as a fixed offset.29 Variables significant in univariate analysis or most biologically relevant for developing or dying from lung cancer were entered into the multivariate Poisson models. In addition to anti-estrogen treatment, we included age and period at diagnosis, estrogen receptor status, radiotherapy and chemotherapy use. The model fitted for the SMRs did not include estrogen receptor status, as the variable had strata with 0 events.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Of the 6655 breast cancer patients, 3066 (46%) received anti-estrogen therapy and 3589 (54%) did not (Table 1). Anti-estrogen therapy was more frequently administered in the most recent period of the study (86% in 1991-2003). Compared with women without hormonal therapy, those with anti-estrogen therapy were significantly older (mean age at diagnosis 64 and 60 years, respectively; P < .001) and postmenopausal (79% and 68%, respectively; P < .001). As expected, tumors of women who received anti-estrogen therapy were more likely to express estrogen and progesterone receptors. Women with anti-estrogen therapy more often underwent radiotherapy and less often underwent surgery or chemotherapy than women without anti-estrogens.

Table 1. Characteristics of Breast Cancer Patients by Anti-estrogen Therapy Use. Geneva Cancer Registry, 1980-2003.
Patient characteristicsAnti-estrogen Therapy
Yes (n = 3066)No (n = 3589)Pa
No.%No.%
  • Percentages are of nonmissing data. Numbers may not sum to 100% due to rounding and missing data.

  • a

    Chi-square test for heterogeneity.

  • b

    Recorded since 1995.

  • c

    Recorded since 1990.

      
Period of cancer diagnosis    <.001
 1980-199041714206157 
 1991-2003264986152843 
Method of detection    <.001
 Symptoms77725201556 
 Clinical examination or screening10593562617 
 Other12304094826 
Age, y, at diagnosis    <.001
 <408032367 
 40-493471179922 
 50-597782588225 
 60-697982668219 
 70-795982060217 
 <804651538811 
Menopausal statusb    <.001
 Pre- and peri-4352129332 
 Post16757961468 
Civil status    <.001
 Single4201449014 
 Married147448193954 
 Widowed7142365218 
 Separated4581550814 
Social class    .130
 Low4251739515 
 Middle151359155359 
 High6162468526 
Familial riskc    .077
 None180571106474 
 Moderate5612229320 
 High1657745 
Tumor characteristics     
 Stage    .083
  I105736124437 
  II135146152246 
  III3201137711 
  IV22171996 
 Histological subtype    <.001
  Ductal225876278780 
  Lobular362122066 
  Other3701250514 
 Differentiation    <.001
  Good8193347423 
  Moderate12234989844 
  Poor4571867633 
 Diameter    .493
  1 - 20 mm147261173360 
  21 - 40 mm7493193632 
  > 40 mm19682208 
 Estrogen receptor statusb    <.001
  Positive19569739351 
  Negative63338549 
 Progesterone receptor statusb    <.001
  Positive15927932542 
  Negative4302145458 
Treatment     
 Radiotherapy    <.001
  No100533185352 
  Yes206167173648 
 Surgery    <.001
  No4821636910 
  Yes258484322090 
 Chemotherapy    0.28
  No209068235566 
  Yes97632123434 

From medical records, we retrieved data on tobacco use for 3322 women, ie, 50% of the study population (Table 2). Approximately 57% of the missing data applied to women with breast cancer diagnosed during the first part of the study period. The proportion of never smokers was very similar among women who received anti-estrogen therapy (63%) and those who did not (65%), and no differences were found between the 2 groups of therapy, neither for smoking status (former or current) nor for the number of pack-years smoked.

Table 2. Smoking Status of Breast Cancer Patients According to Anti-Estrogen Use
 Anti-estrogen Therapy 
YesNo
n=2105n=1217
No.%No.%P
  • a

    Chi-square test for heterogeneity between never smokers and ever smokers.

  • b

    Percentages are calculated among ever smokers.

  • c

    Chi-square test for heterogeneity between former and current smokers.

  • d

    Among current smokers.

Smoking status at time of cancer diagnosis     
Never smoker13256378565.367a
Ever smoker7803743235 
 Former smoker28436b14333b.249c
 Current smoker49664b28967b 
Pack-years of smokingd    1.00
 1-201814210842 
 21-40155369236 
 >4093225522 

The median follow-up period for the whole cohort was 7.3 years. The cohort yielded 57,257 person-years (21,677 among anti-estrogen users and 35,580 in nonusers). From July 1980 until December 2007, we observed a total of 40 lung cancer cases occurring at least 6 months after breast cancer diagnosis. The incidence rate of lung cancer was 55.4 per 100,000 person-years for women with anti- estrogens versus 78.8 per 100,000 for women without (P = .39; Table 3). Compared with the general population, the risk (SIR) of developing lung cancer among women who received anti-estrogens was 0.63 (95% CI, 0.33-1.10) and among women without anti-estrogens 1.12 (95% CI, 0.74-1.62; Table 3). Lung cancer mortality rates were 9.2 of 100,000 for women with anti-estrogens and 45.0 of 100,000 for women without anti-estrogens (P = .026; Table 4). Compared with the general population, lung cancer mortality risk (SMR) was 0.13 (95% CI, 0.02-0.47) among women who received anti-estrogens (P < .001) and 0.76 (95% CI, 0.43-1.23) among women who did not. The SIR predicted from the multivariate Poisson regression model, adjusted for age and period at diagnosis, estrogen-receptor status, and radiotherapy use, was 1.60 (95% CI, 0.21-12.1) for women with anti-estrogen and 2.47 (95% CI, 0.48-12.7) for women without. The SMRs adjusted for the same variables, except estrogen receptor status, did not change markedly from those in the univariate analysis, indicating that these results are likely not due to confounding variables. In particular, the SMR for women with anti-estrogens was 0.14 (95% CI, 0.02-1.23), and the SMR for women without anti-estrogens was 0.88 (0.23-3.41). All the estimates were no longer significant.

Table 3. Risk of Lung Cancer After Breast Cancer Among Women With and Without Anti-Estrogens. Geneva Cancer Registry 1980-2003
Anti-estrogen TherapyIncidence RatesaObserved CasesExpected CasesSIR95% CIP
  • SIR indicates age-standardized incidence ratio; CI, confidence interval.

  • a

    Age-standardized (Geneva population distribution) incidence rates per 100,000 person-years.

Yes55.41219.10.630.33-1.10.116
No78.82825.01.120.74-1.62.600
Table 4. Risk of Mortality From Lung Cancer After Breast Cancer Among Women With and Without Anti-Estrogen Use. Geneva Cancer Registry 1980-2003
Anti-estrogen TherapyMortality RatesaObserved CasesExpected CasesSMR95% CIP
  • SMR indicates age-standardized mortality ratio; CI, confidence interval.

  • a

    Age-standardized (Geneva population distribution) mortality rates per 100,000 person-years.

Yes9.2215.30.130.02-0.47<.001
No45.01621.10.760.43-1.23.316

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

In analyses comparing tumor registry to population results from standardized mortality ratios, we found that anti-estrogen treatment for breast cancer was associated with a reduced risk of death from lung cancer, providing new evidence on the role of estrogen in lung cancer progression. These findings are unlikely attributable to smoking differences, as the exposure to tobacco among women who received anti-estrogen therapy and those who did not was almost identical. In addition, patterns of tobacco use in our study population (never smokers 57%, former smokers 14%, and current smokers 29%) were very comparable to that of the general female population of Switzerland in 2003 (55%, 16%, and 29%, respectively).30 However, we retrieved information on smoking history for approximately only half of the study population. Also, we have no information on changes in smoking habits after the breast cancer diagnosis. Missing information mainly applied to older women diagnosed in the years 1980-1990. Because smoking was uncommon in the Swiss female population 2 to 3 decades ago, it is likely that most of the women with missing data on smoking were never smokers. Indeed, when stratifying by tobacco use, we found that women with unknown smoking status presented with lung cancer incidence rates similar to never smokers. For women with anti-estrogens, the SIRs among never smokers and women with unknown smoking status were 0.35 (95% CI, 0.07-1.02) and 0.33 (95% CI, 0.04-1.19), respectively. For women without anti-estrogens, the correspondent SIRs were 0.55 (95% CI, 0.11-1.61) and 0.47 (95% CI, 0.20-0.93), respectively. These findings, plus the results of our sensitivity analysis only considering women diagnosed after 1990, confirm that differences in smoking exposure cannot explain our results. A limitation of our study comes from the type of analytical approach used to compare Cancer Registry data with results expected in the general population, which can also be subject to potential, random variations and confounding. Additional limitations of this study include the few number of events, possible biases and misclassifications of data, incomplete data, and lacking type, dosage, and duration of anti-estrogen. Strengths of the study are its prospective design in a population-based cohort and the accuracy of death certificates because trained tumor registrars establish both the cause of death and the presence of the tumor at death for all diseased patients by systematically consulting clinical records and/or interpreting questionnaires filled in by the patient's physician.

Like other studies, we found no significant association between lung cancer incidence and anti-estrogen therapy.31 However, we cannot exclude a protective role of anti-estrogens on lung cancer risk, as women with anti-estrogens presented a nonsignificant lower risk of developing lung cancer, despite that another well-known lung cancer risk factor, radiotherapy, was more often given to women with anti-estrogen therapy than to women without (67% vs 48%). The small sample size and the short follow-up could be partly responsible for this lack of results.

The decreased risk of death from lung cancer among women who received anti-estrogens is compatible with the findings of higher lung cancer mortality rates among menopausal hormone users reported by recent studies.9, 20, 21

The association between hormone replacement therapy (HRT) and higher lung cancer mortality rates has not always been observed. A lack of association was found in 2 studies,22, 31, 32 whereas a protective effect of HRT on lung cancer mortality was reported in another 2 studies.16, 23 This apparent lack of coherence may be explained by the use of diverse study designs and important differences in smoking levels among the examined populations. In fact, HRT seems to act as a risk factor or prognostic factor of lung cancer only among smokers,12, 14, 16, 21 or more importantly, type of HRT used. Indeed, it has recently been determined that the effect of HRT is different according to its formulation, with estrogen plus progesterone combination being associated with increased lung cancer incidence9 and mortality,20 whereas no association has been found with estrogen alone.22

From a biological perspective, the observations that estrogen intake is associated with increased lung cancer mortality21, 24, 25 and that anti-estrogen treatment is associated with a decreased lung cancer mortality, as demonstrated in this study, strongly suggest that estrogens are involved in lung cancer progression. Previous studies have reported that a great majority of NSCLC, which represents the majority of lung cancer cases, expressed estrogen receptors (ER) alpha and beta.6–8, 32 Experimental studies have also shown that estrogens stimulate NSCLC cells through ER-mediated signaling5,7, 8 and that anti-estrogens, such as tamoxifen or raloxifene, inhibit tumor growth induced by estrogen.6, 33 A study examining the level of protein expression of aromatase in 422 patients with NSCLC reported an association between a high level of aromatase expression and worse lung cancer prognosis.34 Finally, a recent study found several associations between single-nucleotide polymorphisms in a set of genes involved in the pathways of sex steroid synthesis and development of NSCLC in women.35

Our a priori hypothesis was that if estrogens have a real detrimental effect on lung cancer outcome, then anti-estrogens would affect lung cancer prognosis. Albeit comparisons across 2 separate populations should require cautious interpretation, our results show that breast cancer patients who received anti-estrogens have a decrease in lung cancer mortality, reinforcing the evidence that estrogen plays a key role in lung cancer progression. Existing large randomized clinical trials for adjuvant breast cancer therapy and for primary prevention with tamoxifen are the ideal settings for more definitive assessment regarding the role of anti estrogens on lung cancer outcome.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

We thank Stina Blagojevic, for technical and editorial assistance, and the Cancer Registry team for providing data and support.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES
  • 1
    Cancer Incidence in Five Continents, Vol IX. IARC Scientific Publications no 160. Lyon: International Agency for Research on Cancer; 2008.
  • 2
    Bouchardy C, Neyroud-Caspar I, Keller Mighali J, Usel M. Le Cancer a Geneve –Incidence, Mortalite, Survie et Prevalence 2003-2006. http://asrt.ch/rgt/publication_1970_2006.pdf. Accessed February 24, 2010.
  • 3
    Dougherty SM, Mazhawidza W, Bohn AR, et al. Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells. Endocr Relat Cancer. 2006; 13: 113134.
  • 4
    Ivanova MM, Mazhawidza W, Dougherty SM, Minna JD, Klinge CM. Activity and intracellular location of estrogen receptors alpha and beta in human bronchial epithelial cells. Mol Cell Endocrinol. 2009; 305: 1221.
  • 5
    Dubey S, Siegfried JM, Traynor AM. Non-small-cell lung cancer and breast carcinoma: chemotherapy and beyond. Lancet Oncol. 2006; 7: 416424.
  • 6
    Niikawa H, Suzuki T, Miki Y, et al. Intratumoral estrogens and estrogen receptors in human non-small cell lung carcinoma. Clin Cancer Res. 2008; 14: 44174426.
  • 7
    Stabile LP, Lyker JS, Gubish CT, Zhang W, Grandis JR, Siegfried JM. Combined targeting of the estrogen receptor and the epidermal growth factor receptor in non-small cell lung cancer shows enhanced antiproliferative effects. Cancer Res. 2005; 65: 14591470.
  • 8
    Stabile LP, Davis AL, Gubish CT, et al. Human non-small cell lung tumors and cells derived from normal lung express both estrogen receptor alpha and beta and show biological responses to estrogen. Cancer Res. 2002; 62: 21412150.
  • 9
    Slatore CG, Chien JW, Au DH, Satia JA, White E. Lung cancer and hormone replacement therapy: association in the Vitamins and Lifestyle Study. J Clin Oncol. 2010; 28: 15401546.
  • 10
    Liu Y, Inoue M, Sobue T, Tsugane S. Reproductive factors, hormone use and the risk of lung cancer among middle-aged never-smoking Japanese women: a large-scale population-based cohort study. Int J Cancer. 2005; 117: 662666.
  • 11
    Adami HO, Persson I, Hoover R, Schairer C, Bergkvist L. Risk of cancer in women receiving hormone replacement therapy. Int J Cancer. 1989; 44: 833839.
  • 12
    Taioli E, Wynder EL. Re: Endocrine factors and adenocarcinoma of the lung in women. J Natl Cancer Inst. 1994; 86: 869870.
  • 13
    Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002; 288: 321333.
  • 14
    Kreuzer M, Gerken M, Heinrich J, Kreienbrock L, Wichmann HE. Hormonal factors and risk of lung cancer among women? Int J Epidemiol. 2003; 32: 263271.
  • 15
    Olsson H, Bladstrom A, Ingvar C. Are smoking-associated cancers prevented or postponed in women using hormone replacement therapy? Obstet Gynecol. 2003; 102: 565570.
  • 16
    Schabath MB, Wu X, Vassilopoulou-Sellin R, Vaporciyan AA, Spitz MR. Hormone replacement therapy and lung cancer risk: a case-control analysis. Clin Cancer Res. 2004; 10: 113123.
  • 17
    Schwartz AG, Wenzlaff AS, Prysak GM, et al. Reproductive factors, hormone use, estrogen receptor expression and risk of non small-cell lung cancer in women. J Clin Oncol. 2007; 25: 57855792.
  • 18
    Chen KY, Hsiao CF, Chang GC, et al. Hormone replacement therapy and lung cancer risk in Chinese. Cancer. 2007; 110: 17681775.
  • 19
    Baik CS, Strauss GM, Speizer FE, Feskanich D. Reproductive factors, hormone use, and risk for lung cancer in postmenopausal women, the nurses' health study. Cancer Epidemiol Biomarkers Prev. In press.
  • 20
    Chlebowski RT, Schwartz AG, Wakelee H, et al. Oestrogen plus progestin and lung cancer in postmenopausal women (Women's Health Initiative trial): a post-hoc analysis of a randomised controlled trial. Lancet. 2009; 374: 12431251.
  • 21
    Ganti AK, Sahmoun AE, Panwalkar AW, Tendulkar KK, Potti A. Hormone replacement therapy is associated with decreased survival in women with lung cancer. J Clin Oncol. 2006; 24: 5963.
  • 22
    Chlebowski RT, Anderson GL, Manson JE, et al. Lung cancer among postmenopausal women treated with estrogen alone in the women's health initiative randomized trial. J Natl Cancer Inst 2010; 102: 14131421.
  • 23
    Ettinger B, Friedman GD, Bush T, Quesenberry CP Jr. Reduced mortality associated with long-term postmenopausal estrogen therapy. Obstet Gynecol. 1996; 87: 612.
  • 24
    Ayeni O, Robinson A. Hormone replacement therapy and outcomes for women with non-small-cell lung cancer: can an association be confirmed? Curr Oncol. 2009; 16: 21-25.
  • 25
    Huang B, Carloss H, Wyatt SW, Riley E. Hormone replacement therapy and survival in lung cancer in postmenopausal women in a rural population. Cancer. 2009; 115: 41674175.
  • 26
    Fritz A, Percy C, Jack A, et al. eds. ICD-O International Classification of Diseases for Oncology, 3rd Edition. Geneva: World Health Organization; 2000.
  • 27
    World Health Organization (WHO), eds. ICD-10. International Statistical Classification of Diseases and Health Related Problems, 10th Revision. Geneva: World Health Organization; 1992.
  • 28
    Sobin LH, Wittekind Ch, eds. TNM Classification Of Malignant Tumours, 6th Edition. New York: UICC; 2002.
  • 29
    Breslow NE, Day NE. Statistical Methods in Cancer Res. Vol I: The Analysis of Case-Control Studies. IARC Scientific Publications no 32. Lyon: International Agency for Research on Cancer; 1980.
  • 30
    Keller R, Kutter, B., Krebs H, Hornung R. Tabakmonitoring. Bericht uber den Tabakkonsum der Schweizer Wohnbevolkerung in den Jahren 2001 und 2002. Zurich: Psychologisches Institut der Universitat Zurich, Sozialpsychologie II; 2003.
  • 31
    Patel JD, Gray RG, Stewart JA, Skinner HG, Schiller JH. Tamoxifen does not reduce the risk of lung cancer in women. Available at: http://www.asco.org/ASCOv2/Meetings/Abstracts? &vmview=abst_detail_view&confID=34&abstractID=32861. Accessed July 1, 2009.
  • 32
    Raso MG, Behrens C, Herynk MH, et al. Immunohistochemical expression of estrogen and progesterone receptors identifies a subset of NSCLCs and correlates with EGFR mutation. Clin Cancer Res. 2009; 15: 53595368.
  • 33
    Weinberg OK, Marquez-Garban DC, Fishbein MC, et al. Aromatase inhibitors in human lung cancer therapy. Cancer Res. 2005; 65: 1128711291.
  • 34
    Mah V, Seligson DB, Li A, et al. Aromatase expression predicts survival in women with early-stage non small cell lung cancer. Cancer Res. 2007; 67: 1048410490.
  • 35
    Cote ML, Yoo W, Wenzlaff AS, et al. Tobacco and estrogen metabolic polymorphisms and risk of non-small cell lung cancer in women. Carcinogenesis. 2009; 30: 626635.