Lung cancer mortality risk among breast cancer patients treated with anti-estrogens

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Article

Reference

Lung cancer mortality risk among breast cancer patients treated with anti-estrogens

BOUCHARDY MAGNIN, Christine, et al.

Abstract

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.

BOUCHARDY MAGNIN, Christine, et al . Lung cancer mortality risk among breast cancer patients treated with anti-estrogens. Cancer , 2011, vol. 117, no. 6, p. 1288-95

PMID : 21264820

DOI : 10.1002/cncr.25638

Available at:

http://archive-ouverte.unige.ch/unige:24416

Disclaimer: layout of this document may differ from the published version.

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Lung Cancer Mortality Risk Among Breast Cancer Patients Treated With Anti-Estrogens

Christine Bouchardy, MD¹; Simone Benhamou, DSc^2,3; Robin Schaffar, MSc¹; Helena M. Verkooijen, MD^1,4; Gerald Fioretta, MSc¹; Hyma Schubert, MSc¹; Vincent Vinh-Hung, MD⁵; Jean-Charles Soria, MD⁶; Georges Vlastos, MD⁷; and Elisabetta Rapiti, MD¹

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.Cancer2011;000:000–000.V^C 2011 American Cancer Society.

KEYWORDS:lung cancer, breast cancer, mortality risk, anti-estrogens, epidemiology, population-based study.

The

incidence of lung cancer has increased strongly among women in Switzerland and other industrialized countries because of the smoking epidemic among young women.¹Despite treatment progress, survival remains poor with only

<16% of patients surviving more than 5 years after diagnosis.²Although 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,^3,4and experimental studies report grow- ing evidence that estrogens may promote lung tumor occurrence and progression.^5-8However, studies evaluating the association between menopausal hormone use containing estrogen alone, or combined estrogen and progestin and lung cancer incidence^9-20or mortality,^16,20-25provide conflicting results. Results from randomized controlled trials showed similar risk of lung cancer incidence^13,20but 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

DOI:10.1002/cncr.25638,Received:April 13, 2010;Revised:June 21, 2010;Accepted:June 30, 2010,Published onlinein Wiley Online Library (wileyonlinelibrary.com)

Corresponding author:Christine Bouchardy, MD, Geneva Cancer Registry, 55 Boulevard de la Cluse, 1205 Geneva, Switzerland; Fax: (011) 41 22 379 49 71;

christine.bouchardymagnin@unige.ch

1Geneva Cancer Registry, Institute for Social and Preventive Medicine, University of Geneva, Geneva, Switzerland;²INSERM, U946, Paris, France;³CNRS UMR 8200, Gustave-Roussy Institute, Villejuif, France;⁴Department of Epidemiology and Public Health, National University of Singapore, Singapore;⁵Division of Radiation Oncology, Geneva University Hospitals, Geneva, Switzerland;⁶Division of Cancer Medicine, Gustave-Roussy Institute, Villejuif, France;⁷Senology Unit, Department of Gynecology and Obstetrics, Geneva University Hospitals, Geneva, Switzerland

This study was an oral presentation at the 32^ndAnnual San Antonio Breast Cancer Symposium, December 9-13, 2009 in San Antonio, Texas.

CB, SB, and ER contributed to the study design, oversaw the project, and drafted the final manuscript. HS was responsible for data collection. RS and GF were responsible for statistical analyses. HMV, JCS, VVH, and GV advised on the analysis and participated in data interpretation. All authors critically reviewed the manuscript

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

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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 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.¹All 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 Clas- sification of Diseases for Oncology, ICD-O),²⁶hormone 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 registra- tion 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 (n¼60). 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 adminis- trative 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 patho- logic 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 rou- tinely recorded in the cancer registry database, we retro- spectively extracted this data from medical files. Women were classified as never or ever smokers and within the lat- ter 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).

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Table 1.Characteristics of Breast Cancer Patients by Anti-estrogen Therapy Use. Geneva Cancer Registry, 1980-2003.

Patient characteristics

Anti-estrogen Therapy Yes (n53066) No (n53589)

P^a

No. % No. %

Period of cancer diagnosis <.001

1980-1990 417 14 2061 57

1991-2003 2649 86 1528 43

Method of detection <.001

Symptoms 777 25 2015 56

Clinical examination or screening 1059 35 626 17

Other 1230 40 948 26

Age, y, at diagnosis <.001

<40 80 3 236 7

40-49 347 11 799 22

50-59 778 25 882 25

60-69 798 26 682 19

70-79 598 20 602 17

<80 465 15 388 11

Menopausal status^b <.001

Pre- and peri- 435 21 293 32

Post 1675 79 614 68

Civil status <.001

Single 420 14 490 14

Married 1474 48 1939 54

Widowed 714 23 652 18

Separated 458 15 508 14

Social class .130

Low 425 17 395 15

Middle 1513 59 1553 59

High 616 24 685 26

Familial risk^c .077

None 1805 71 1064 74

Moderate 561 22 293 20

High 165 7 74 5

Tumor characteristics

Stage .083

I 1057 36 1244 37

II 1351 46 1522 46

III 320 11 377 11

IV 221 7 199 6

Histological subtype <.001

Ductal 2258 76 2787 80

Lobular 362 12 206 6

Other 370 12 505 14

Differentiation <.001

Good 819 33 474 23

Moderate 1223 49 898 44

Poor 457 18 676 33

Diameter .493

1 - 20 mm 1472 61 1733 60

21 - 40 mm 749 31 936 32

>40 mm 196 8 220 8

(Continued)

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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 de- parture 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

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.

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

Table 1. (Continued)

Patient characteristics

Anti-estrogen Therapy Yes (n53066) No (n53589)

P^a

No. % No. %

Estrogen receptor status^b <.001

Positive 1956 97 393 51

Negative 63 3 385 49

Progesterone receptor status^b <.001

Positive 1592 79 325 42

Negative 430 21 454 58

Treatment

Radiotherapy _<.001

No 1005 33 1853 52

Yes 2061 67 1736 48

Surgery _<.001

No 482 16 369 10

Yes 2584 84 3220 90

Chemotherapy 0.28

No 2090 68 2355 66

Yes 976 32 1234 34

Percentages are of nonmissing data. Numbers may not sum to 100% due to rounding and missing data.

aChi-square test for heterogeneity.

bRecorded since 1995.

cRecorded since 1990.

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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.

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 non- users). 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 (P¼.39; 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 with-

out 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 ¼ .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-

Table 2.Smoking Status of Breast Cancer Patients According to Anti-Estrogen Use

Anti-estrogen Therapy

Yes No

n52105 n51217

No. % No. % P

Smoking status at time of cancer diagnosis

Never smoker 1325 63 785 65 .367^a

Ever smoker 780 37 432 35

Former smoker 284 36^b 143 33^b .249^c

Current smoker 496 64^b 289 67^b

Pack-years of smoking^d 1.00

1-20 181 42 108 42

21-40 155 36 92 36

>40 93 22 55 22

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

bPercentages are calculated among ever smokers.

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

dAmong current smokers.

Table 3.Risk of Lung Cancer After Breast Cancer Among Women With and Without Anti-Estrogens. Geneva Cancer Registry 1980-2003

Incidence Rates^a

Observed Cases

Expected Cases

SIR 95% CI P

Yes 55.4 12 19.1 0.63 0.33-1.10 .116

No 78.8 28 25.0 1.12 0.74-1.62 .600

SIR indicates age-standardized incidence ratio; CI, confidence interval.

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

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estrogens was 0.88 (0.23-3.41). All the estimates were no longer significant.

DISCUSSION

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 com- parable to that of the general female population of Swit- zerland 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 pre- sented 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 con- sidering 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 misclassifica- tions 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 pres- ence 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 pre- sented 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,^22,31,32whereas 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

Table 4.Risk of Mortality From Lung Cancer After Breast Cancer Among Women With and Without Anti-Estrogen Use. Geneva Cancer Registry 1980-2003

Mortality Rates^a

Observed Cases

Expected Cases

SMR 95% CI P

Yes 9.2 2 15.3 0.13 0.02-0.47 <.001

No 45.0 16 21.1 0.76 0.43-1.23 .316

SMR indicates age-standardized mortality ratio; CI, confidence interval.

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

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according to its formulation, with estrogen plus progesterone combination being associated with increased lung cancer incidence⁹and mortality,²⁰whereas no association has been found with estrogen alone.²²

From a biological perspective, the observations that estrogen intake is associated with increased lung cancer mortality^21,24,25and that anti-estrogen treatment is associated with a decreased lung cancer mortality, as demon- strated in this study, strongly suggest that estrogens are involved in lung cancer progression. Previous studies have reported that a great majority of NSCLC, which repre- sents the majority of lung cancer cases, expressed estrogen receptors (ER) alpha and beta.^6-8,32Experimental 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 com- parisons across 2 separate populations should require cau- tious 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.

CONFLICT OF INTEREST DISCLOSURES

The authors made no disclosures.

REFERENCES

1. Cancer Incidence in Five Continents, Vol IX. IARC Scien- tific 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 Preva- lence 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;13:113–134.

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;305:12–21.

5. Dubey S, Siegfried JM, Traynor AM. Non-small-cell lung cancer and breast carcinoma: chemotherapy and beyond.

Lancet Oncol.2006;7:416–424.

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;14:4417–4426.

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;65:1459–1470.

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;62:2141–2150.

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:

1540–1546.

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;117:662–666.

11. Adami HO, Persson I, Hoover R, Schairer C, Bergkvist L.

Risk of cancer in women receiving hormone replacement therapy.Int J Cancer.1989;44:833–839.

12. Taioli E, Wynder EL. Re: Endocrine factors and adenocarcinoma of the lung in women.J Natl Cancer Inst.1994;86: 869–870.

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:

321–333.

14. Kreuzer M, Gerken M, Heinrich J, Kreienbrock L, Wich- mann HE. Hormonal factors and risk of lung cancer among women? Int J Epidemiol.2003;32:263–271.

15. Olsson H, Bladstrom A, Ingvar C. Are smoking-associated cancers prevented or postponed in women using hormone replacement therapy? Obstet Gynecol.2003;102:565–570.

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;

10:113–123.

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;25:5785–5792.

18. Chen KY, Hsiao CF, Chang GC, et al. Hormone replacement therapy and lung cancer risk in Chinese. Cancer.

2007;110:1768–1775.

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;374:1243–1251.

(9)

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;24:59–63.

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 Inst2010;102:1413–1421.

23. Ettinger B, Friedman GD, Bush T, Quesenberry CP Jr.

Reduced mortality associated with long-term postmenopausal estrogen therapy.Obstet Gynecol.1996;87:6–12.

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;115:4167–4175.

26. Fritz A, Percy C, Jack A, et al. eds. ICD-O International Classification of Diseases for Oncology, 3rd Edition. Ge- neva: World Health Organization; 2000.

27. World Health Organization (WHO), eds. ICD-10. Interna- tional Statistical Classification of Diseases and Health Related Problems, 10th Revision. Geneva: World Health Organization; 1992.

28. Sobin LH, Wittekind Ch, eds. TNM Classification Of Ma- lignant 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 Scien- tific Publications no 32. Lyon: International Agency for Research on Cancer; 1980.

30. Keller R, Kutter, B., Krebs H, Hornung R. Tabakmonitor- ing. Bericht uber den Tabakkonsum der Schweizer Wohnbe- volkerung in den Jahren 2001 und 2002. Zurich:

Psychologisches Institut der Universitat Zurich, Sozialpsy- chologie 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?

&vmview¼abst_detail_view&confID¼34&abstractID¼32861.

Accessed July 1, 2009.

32. Raso MG, Behrens C, Herynk MH, et al. Immunohisto- chemical expression of estrogen and progesterone receptors identifies a subset of NSCLCs and correlates with EGFR mutation.Clin Cancer Res.2009;15:5359–5368.

33. Weinberg OK, Marquez-Garban DC, Fishbein MC, et al.

Aromatase inhibitors in human lung cancer therapy.Cancer Res.2005;65:11287–11291.

34. Mah V, Seligson DB, Li A, et al. Aromatase expression pre- dicts survival in women with early-stage non small cell lung cancer.Cancer Res.2007;67:10484–10490.

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;30:626–635.

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