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Ann Thorac Surg 2003;76:1789-1795
© 2003 The Society of Thoracic Surgeons

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Original article: general thoracic

Menopausal effects on presentation, treatment, and survival of women with non–small cell lung cancer

^a Division of Thoracic Surgery, Department of General Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
^b Division of Thoracic Surgery, Department of General Surgery, Mount Sinai Medical Center and Mount Sinai School of Medicine, New York, New York, USA

^* Address reprint requests to Dr Lukanich, Division of Thoracic Surgery, Department of General Surgery, Brigham and Women's Hospital, 75 Francis St, Boston, MA, USA 02115
e-mail: jlukanich{at}partners.org

Presented at the Poster Session of the Thirty-eighth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28–30, 2002.

	Abstract

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BACKGROUND: Small population studies have reported higher survival rates for women than men with non–small cell lung carcinoma (NSCLC). Because human NSCLC cells express estrogen receptors, we evaluated hormonally active and inactive women to identify biologically mediated differences.

METHODS: A total of 14,676 US women with stage I through IV primary non–small cell lung cancer (NSCLC) from the 1992 to 1997 Surveillance, Epidemiology, and End Results database were grouped into two categories based on the average menopausal age of 51 years as defined by the American College of Obstetricians and Gynecologists: ages 31 to 50 premenopausal (n = 2,230, 15%) and ages 51 to 70 postmenopausal (n = 12,446, 85%). Extreme ages were excluded. Statistics were calculated with ² or Mann-Whitney tests, Kaplan–Meier estimates with log-rank tests, and Cox proportional hazards models.

RESULTS: Premenopausal women more commonly presented with advanced clinical stage, less favorable histology (adenocarcinoma), and poorly differentiated tumors, and more often underwent pneumonectomies. Surgery with curative intent was performed in 31% premenopausal and 33% postmenopausal women (p = 0.03). Overall survival for premenopausal and postmenopausal women was not significantly different (median 10 and 9 months, all stages; 70 and 71 months, stages I and II). Adjusting for significant covariates (stage, histology, size, grade, extent of surgery), postmenopausal women had higher lung-cancer–related deaths (hazard ratio, 1.14; 95% confidence interval, 1.03 to 1.27).

CONCLUSIONS: Premenopausal women presented more often with advanced disease and underwent more extensive resection, yet had survival advantage after covariate adjustment. Additionally, postmenopausal women had a survival advantage compared with their male counterparts. Results suggest that estrogen exposure creates a milieu that may confer a protective effect through some yet unknown mechanisms that determine outcome of the neoplastic process and warrant further investigation.

	Introduction

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Lung cancer is the leading cause of mortality in men and women in the United States [1]. Of the 169,500 new cases of lung cancer diagnosed in 2001, 46% were projected to be in women. Overall, the 5-year survival rate for lung cancer is low at 15.8% because of the advanced stage of most patients at presentation [2]. Small retrospective population studies have reported higher survival rates for women than similarly staged men with non–small cell lung cancer (NSCLC) [3–7]. Yet women are more likely to be asymptomatic, to be nonsmokers, to present with adenocarcinoma (a less favorable histology), to not have a histologic diagnosis obtained during preoperative bronchoscopy, and to undergo fewer pneumonectomies [7]. Why do women present unfavorably, yet carry a more favorable prognosis? Are there any protective effects linked to the female sex that are present in early stage [7] or advanced disease [8]?

One sex difference that may account for variations in presentation and survival between women and men may be the effect of menopausal status. In the cardiovascular system, the protective effects of female sex have been attributed to estrogen, which alters serum lipid states and directly acts on blood vessels [9]. However, the estrogen receptor, as with all steroid hormone receptors, is a transcription modulator that alters gene expression when activated. In breast cancer, for example, estrogen receptor-mediated signal transduction increases cell proliferation, which is accompanied by an increased probability for DNA mutations to occur.

Some evidence suggests that estrogen plays an important role in NSCLC, although the exact role is unknown. We know that human NSCLC cells express an abundance of estrogen receptors [10]. In fact, estrogen levels are often elevated in lung cancer patients [4]. Even in estrogen receptor-negative lung cancer cells, tamoxifen has been shown to inhibit cell proliferation in vitro [11]. Additionally, clinical research in early stage adenocarcinoma suggests that there may be a significant association among female sex, K-ras mutation, and decreased patient survival, thereby raising the question of the role of estrogen exposure in initiation or selection of K-ras mutant clones [12].

Steroid sex hormones may promote carcinogenesis in hormone-dependent tissues [13]. A retrospective study comparing lung cancer patients by age at diagnosis revealed a higher percentage of women in the younger group (< 50 years) than in the older group (39% versus 28%), most of whom had adenocarcinoma [14]. There are also seemingly conflicting data showing that women on long-term estrogen replacement therapy have an increased risk of developing lung cancer [15] as well as a decreased risk of death from it [16]. These findings illustrate the complexity of effects estrogen may have on lung cancer development. Estrogen may provide either protective, adverse, or combined effects in women with regard to lung cancer, as is noted in breast cancer. At this time, no large cohort has been studied to examine the effect of the estrogen cycle, or menopausal status, on lung cancer outcomes.

With this study, we sought to identify whether differences in the presentation, treatment, and survival of women with primary NSCLC were due to the effect of the menopausal status (using age as a proxy) using a large multi-institutional database.

	Material and methods

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From 1992 to 1997, 137,592 primary lung cancers were registered in the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute (1.45:1 male:female ratio, average age 67.9 ± 11 years). The SEER program is the only large-scale source of population-based information in the United States that includes stage of cancer at the time of diagnosis and survival rates within each stage. SEER collects and publishes cancer incidence and survival data from 11 cancer registries across the United States (ie, San Francisco-Oakland, San Jose-Monterey, Los Angeles, Hawaii, Seattle [Puget Sound], New Mexico, Utah, Iowa, Metropolitan Detroit, Metropolitan Atlanta, and Connecticut). Covering approximately 14% of the US population, the SEER sample is comparable to the general population with regard to education and wealth but is slightly more urban and has a higher proportion of foreign-born persons compared with the US census. Patient data include demographics, primary tumor site, morphology, stage at diagnosis, first course of treatment, and follow-up for vital status.

The actual cohort analyzed for this study included 14,676 women and 22,841 men (age range 31 to 70 years) with documented stage I through IV primary NSCLC (International Classification of Diseases site codes C34.0–C34.9). The women were grouped into two categories based on the average US menopausal age of 51, as defined by the American College of Obstetricians and Gynecologists: premenopausal (n = 2,230, 15%) was defined as women aged 31 to 50 years and postmenopausal (n = 12,446, 85%) women aged 51 to 70 years. For comparison, men were similarly broken down into two categories: younger men (n = 3022, 13%) aged 31 to 50 years and older men (n = 19,819, 87%) aged 51 to 70 years. Extreme ages (age younger than 30 or older than 70 years) were excluded to reduce the confounding effect of age.

Other potential confounders were compared in premenopausal and postmenopausal categories by ² or Mann-Whitney tests. These categories included race; histology (squamous cell, adenocarcinoma, large cell/undifferentiated, adenosquamous, other [bronchial, sarcoma, lymphoma, melanoma, adenoid cystic, mucoepidermoid]); size (0 to 1 cm, 1 to 3 cm, 3 to 6 cm, > 6 cm); grade; stage; type of surgery (wedge resection, lobectomy, pneumonectomy, biopsy/palliative surgery); curative surgery (yes, no). Their effect on survival was evaluated by Kaplan–Meier estimates with log-rank tests and Cox proportional hazards models. Statistical significance was considered to be p < 0.05.

	Results

Top Abstract Introduction Material and methods Results Comment References

 
A higher percentage of women than men were noted in the 31- to 50-year-old group (42% [2230 of 5252]) than in the 51- to 70-year-old group (39% [12,446 of 32,265]), a finding that is comparable to other studies [14]. Table 1 shows the differences in demographic and tumor characteristics between the premenopausal and postmenopausal groups. There was a significantly higher percentage of African American women among the premenopausal group (18%) than in the postmenopausal group (11%) (p < 0.0001). This demographic shift was compensated for by a change in the percentages of Caucasians in each group, as the percentage of Latina and Asian women remained constant between the groups.

Premenopausal women more commonly presented with poorly differentiated tumors (44%) than postmenopausal women (38%; p < 0.0001). Premenopausal women also presented with more advanced clinical stage than postmenopausal women: 53% of premenopausal women had stage IV disease at the time of diagnosis, compared with only 44% of postmenopausal women. More postmenopausal women (23%) presented with stage I disease compared with premenopausal women (15%) (p < 0.0001). The percentages of premenopausal and postmenopausal women with stages II, IIIA, and IIIB were similar.

Younger and older men presented with a higher percentage of squamous cell cancer (23% and 36%, respectively) and a lower percentage of adenocarcinoma (58% and 49%, respectively) compared with their female counterparts, yet the trend of histologic distribution remained similar to that of the women. Also similar to women, younger men presented with more advanced clinical stage (stage IV) than did older men (55% versus 46%), whereas more older men (18%) presented with stage I disease compared with younger men (15%) (Table 2; p < 0.0001).

Curative surgery, defined as a procedure carried out with the aim to permanently control the malignancy (ie, wedge resection, lobectomy, or pneumonectomy), was performed in 31% of premenopausal and 33% of postmenopausal women (p = 0.03) (Table 3). A slightly higher tendency was noted to undertake wedge resections and lobectomies in postmenopausal women than in premenopausal women. Although premenopausal and postmenopausal women had similar rates of lung resections as shown in Table 3, premenopausal women more commonly underwent pneumonectomies for every stage of resectable cancer than postmenopausal women (p < 0.0001) (Table 4). Additionally, for every stage of disease, premenopausal women underwent radiation therapy more often than postmenopausal women (58% versus 48%, respectively, p < 0.0001) (Table 5).

As illustrated in Figure 1, overall survival for premenopausal and postmenopausal women was not significantly different (overall median survival 10 and 9 months for all stages; 70 and 71 months for stages I and II, respectively; p = NS). Overall median survival for younger and older men was also 9 months for all stages.

View larger version (16K): [in this window] [in a new window]   Fig 1. Kaplan–Meier curves for lung cancer-related survival (months) in premenopausal (—) and postmenopausal ( · · · · · ) women with non–small cell lung carcinoma in all stages (A) and stages I and II (B).

View larger version (17K): [in this window] [in a new window]   Fig 2. (A) Kaplan–Meier curves for lung cancer-related survival (months) in (A) premenopausal women ( · · · · · ) and younger men (—) and (B) postmenopausal women ( · · · · · ) and older men (—) with all stages of non–small cell lung carcinoma. Results indicate a survival advantage for women when compared with their male counterparts.

	Comment

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We used the SEER database, which has been used by other investigators as a representative population of the United States. Our results show premenopausal women more commonly presented with less favorable histology (adenocarcinoma), poorly differentiated tumors, and with advanced clinical stage. Reasons for this finding remain unclear. Traditionally, young women were thought to be at low risk for developing lung cancer. Despite a history of smoking, symptomatology in women is commonly attributed to benign pulmonary processes such as upper respiratory infections, which may further lead to a delay in diagnosis.

One could hypothesize, in the absence of other significant risk factors, that premenopausal women with NSCLC may have disease initiated by higher levels of estrogen. Human NSCLC cells express an abundance of estrogen receptors [10]. In fact, estrogen levels have been shown to be increased in lung cancer patients [4]. This hypothesis is supported by findings of a previous study, which illustrated a significant association between female sex and K-ras mutation in early stage adenocarcinoma [14]. In this way, high estrogen levels could result in deleterious effects in disease presentation of premenopausal women with the K-ras mutation.

African American women presenting with NSCLC were more likely to be premenopausal than postmenopausal. In recent years, the recognition of higher incidence rates for lung cancer among black patients compared with white patients has received increasing public attention. These racial differences have been attributed to a variety of factors, including smoking habits, socioeconomic status, genetic susceptibility, occupational exposure, and diet [17]. Interestingly, in one SEER database study, the overall incidence of lung cancer in black men was 37% higher than in white men, whereas the incidence in black women was only 9% higher than in white women. To our knowledge, no previous study has shown an association of higher rates of lung cancer in younger, premenopausal black women. These racial differences provide an area for further research as the etiology has yet to be determined.

Curative surgery was performed equally in both premenopausal and postmenopausal women. However, premenopausal women more often underwent pneumonectomies for every stage of resectable cancer; possibly due to (a) more aggressive tumors, (b) better preserved cardiopulmonary function, which would permit extensive resection, or (c) the inclination of both the surgeon and the patient to accept the most aggressive treatment in this group of women. An increase in biopsies/palliative surgeries may reflect the desire to establish a diagnosis or treat the symptoms in the younger population.

Despite the differences in presentation, overall survival rates for premenopausal and postmenopausal women were not significantly different. When adjusting for significant covariates (stage, histology, size, grade, extent of surgery), postmenopausal women showed a surprisingly higher rate of lung-cancer–related deaths despite the fact that premenopausal women more often had advanced metastatic stage and worse histology. Our results could suggest that although exposure to estrogen early in life may initiate early stage lung tumorigenesis, lifelong exposure to estrogen at any time during a woman's life may create a milieu that may confer a protective effect through some yet unknown mechanisms that determine outcome of the neoplastic process. It is unclear, however, whether these observations are indeed due to a beneficial hormonal effect of estrogen or if they are a function of age itself or better coping mechanisms for this disease among younger patients.

Previously conducted, small, retrospective population studies have reported higher survival rates for women than similarly staged men with NSCLC [3–7]. In our study, men had a similar median survival rate of 9 months for all stages of disease. Additionally, our results show that premenopausal women and younger men had similar survival rates (HR, 0.99) for all stages, but these men had a trend toward improved survival (HR, 0.87) for stages I and II disease. This finding would indicate that estrogen in fact plays a deleterious role in lung cancer in the younger female patient, especially in early stage disease. However, when both men and women aged 51 to 70 years were compared with premenopausal women, postmenopausal women had a lower incidence of lung-cancer–related deaths than older men for all stages (HR, 1.14 versus 1.26) and early stage disease (HR, 1.28 versus 1.38). This finding again suggests that exposure to estrogen at any time during a woman's life may alter the way the body processes the disease improving their survival with NSCLC.

Due to the nature of the SEER database and the design of this study, it is impossible to eliminate the confounding effect of age on our results; it is clearly one of the most important limitations of the study. The SEER database does not have a category for menopause, which therefore had to be defined using age as a proxy for menopausal status. If our findings were mainly due to the effect of age, one would expect that increased overall and lung cancer-related deaths for older men and postmenopausal women would be the same. However, when age is controlled and both groups are compared with premenopausal women, postmenopausal women have an increased survival advantage, thus supporting the hypothesis that estrogen exposure at any time during a patient's life may confer a protective effect with respect to the outcome of NSCLC.

The incidence, demographics, and histologic presentation of NSCLC have changed dramatically during the past 30 years. One of the advantages of the current study is the accumulation of a large database over a short time interval (6 years). This focused evaluation of data is less susceptible to demographic shifts that occur when studying a changing disease over a longer time period.

Another potential confounder is the inability to determine the use of hormone replacement therapy in postmenopausal women or oral contraceptives in premenopausal or postmenopausal women, as these data were not collected as part of the SEER database. Lack of this information may cloud the menopausal status designations made by splitting the women into two groups by age alone.

Despite its limitations, this study represents a preliminary insight into the complex association that may exist between hormonal factors and lung cancer, and provides us direction for further studies of the role of menopause in the presentation, treatment, and survival of women with NSCLC.

	References

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