the Section of Oncology-Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE
    Department of Internal Medicine, University of North Dakota School of Medicine, Fargo, ND
    Divisions of Hematology and Oncology, Duke University Medical Center, Durham, NC

    ABSTRACT

    PURPOSE: Lung cancer is the leading cause of cancer-related death in women. Hormone replacement therapy (HRT) is frequently prescribed to postmenopausal women, but there is little data on its effect on lung cancer. Hence, we conducted a retrospective study to examine the impact of HRT on the natural history of lung cancer.

    METHODS: We conducted a retrospective chart review of women diagnosed with lung cancer between January 1994 and December 1999. Data collected included age, stage, past history of cancer, smoking history, family history of cancer, HRT use, treatment, and overall survival. The effects of various clinical features on survival were examined using Cox proportional hazards regression models.

    RESULTS: Four hundred ninety-eight women (median age, 67 years; range, 31 to 93 years) with lung cancer were included. A history of smoking was present in 429 women (86%), whereas 86 women (17%) had taken HRT. Women with lung cancer who received HRT were younger than women with lung cancer who never received HRT (63 v 68 years old, respectively; P < .0001). Overall survival was significantly higher in patients with no HRT compared with patients who received HRT (79 v 39 months, respectively; hazard ratio = 1.97; 95% CI, 1.14 to 3.39). This effect seemed to be more pronounced in women with a smoking history.

    CONCLUSION: HRT may affect outcomes from lung cancer adversely. Further studies examining the role of HRT use on outcomes from lung cancer, especially in women with a history of smoking, are urgently needed to clarify this important problem.

    INTRODUCTION

    Lung cancer is currently the leading cause of cancer-related mortality worldwide. In the United States, the American Cancer Society estimates that there will be 172,570 new cases of lung cancer and that 163,510 deaths will occur from lung cancer during 2005.1 Of these new cases, 79,560 will be diagnosed in women. Lung cancer is now the largest cause of cancer-related death in women in the United States, with an estimated 73,020 deaths in 2005. Although the rate of lung cancer–related mortality has started to decline in men since 1990, it has shown an increasing trend in females.2

    The reasons for this sex-related difference in lung cancer mortality are unclear. Some studies have suggested that women are at an increased risk for developing lung cancer because of an underlying variance in genetic alterations compared with males for any given level of smoking.3-5 However, other investigators have reported no such correlation,6, 7 and one study actually found that male smokers are at a higher risk of lung cancer death than women smokers.8

    A factor that is believed to play an important independent role in lung cancer prognosis in women is estrogen, both endogenous and exogenous. In a Swedish, population-based, cohort study, Adami et al9 found that women who used estrogen replacement had a slightly increased risk of developing lung cancer compared with women who did not use estrogen replacement. However, the results were confounded by the fact that there were more smokers in the group of women who used estrogen replacement. In a similar study, Taioli and Wynder10 also found an increased risk of development of adenocarcinoma of the lung in women who used estrogen replacement therapy. Conversely, more recent studies have shown a decreased risk of lung cancer in women using hormone replacement therapy (HRT).11-13

    However, none of these epidemiologic studies addressed the role of estrogen replacement on the outcomes in women with lung cancer. A major question that remained unanswered in these large studies was the impact of HRT on the natural history of lung cancer in women. This study assessed the impact of HRT, with either estrogen alone or in combination with progesterone, on survival in women with a diagnosis of lung cancer.

    METHODS

    After appropriate approval from the institutional review board, we conducted a retrospective review of the medical records of all women diagnosed with lung cancer between January 1994 and December 1999 at a community-based teaching hospital. The following information was abstracted from the patients' charts: age of the patient, symptoms at presentation, stage of the disease at presentation, histologic subtype of lung cancer, past history of other malignancies, smoking history, family history of cancer, use of HRT, treatment received for lung cancer, and overall survival. A minimum of 5 pack years was considered a positive smoking history. All other women were considered as nonsmokers. The majority of the population in our area is white; thus, we limited our analysis to this group.

    The history of HRT use was ascertained from the patients' medication lists and the notes of their primary care physician as documented in their medical charts. The use of HRT was defined to include all forms of hormone replacement, including either combination estrogen and progestin or estrogen alone for at least 6 continuous weeks before the diagnosis of lung cancer. Women who had a history of remote use of HRT for at least 6 weeks were also considered to have used HRT for the purpose of this study. The use of hormonal contraceptives was not considered as HRT use. Premenopausal women were not excluded from this study.

    The statistical methods used included univariate and multivariable Cox proportional hazards regression models to analyze the effect of various clinical parameters on overall survival. The demographic data of women who had used HRT were compared with the data of women who had never used HRT using the log-rank test. P < .05 was considered statistically significant.

    RESULTS

    Four hundred ninety-eight women with lung cancer were included in the study. The median age of the patients was 67 years (range, 31 to 93 years). A previous history of smoking was present in 429 women (86%). One hundred six women (21%) had a previous history of cancer, whereas 329 women (66%) had a family history of malignancy. The demographic features of these patients are listed in Table 1.

    Of the 498 women, 380 (76%) had non–small-cell lung cancer, whereas 117 (24%) had small-cell lung cancer. Among the women who had non–small-cell lung cancer, 157 (41%) had an adenocarcinoma, 133 (35%) had squamous cell carcinoma, 17 (5%) had a large-cell carcinoma, and 65 (14%) had an adenosquamous carcinoma. Five patients had a carcinoid tumor, whereas one patient each had a plasmacytoma and non-Hodgkin's lymphoma.

    Two hundred twenty-two patients (45%) presented with respiratory complaints, including 112 patients (22%) with cough, 66 patients (13%) with shortness of breath, 17 patients (3%) with hemoptysis, seven patients (1%) with change in voice, and 27 patients (5%) with combinations of these symptoms. Seventy-five patients (15%) were asymptomatic and had their disease diagnosed incidentally, whereas 46 patients (9%) had neurologic symptoms, including headache, gait disturbances, visual disturbances, and weakness. Pain was the presenting symptom in 80 patients (16%), whereas 16 patients (3%) had constitutional symptoms of anorexia, weight loss, malaise, generalized weakness, and fever.

    Initial treatment varied depending on the nature and stage of the disease and consisted of a combination of radiation and chemotherapy in 29% of the patients. Ninety-one women (18%) received chemotherapy alone, whereas 109 patients (22%) received radiation alone. Sixty-five patients (13%) underwent surgery alone as treatment for their cancer, whereas 34 patients (7%) received chemotherapy and/or radiation in addition to surgery.

    Eighty-six women (17%) had documented evidence of taking HRT for at least 6 continuous weeks before the development of their lung cancer. Data regarding the use of HRT was not available on 52 women (11%). Women with lung cancer who used HRT were younger (median age, 63 years; range, 31 to 91 years) than women who had never used HRT (median age, 68 years; range, 36 to 93 years; P = .0001). There was no difference between patients receiving HRT by stage at diagnosis of lung cancer (P = .80).

    Overall survival was significantly longer in patients who had never used HRT (median survival, 79 months; 95% CI, 65 to 95 months) compared with patients who had used HRT (median survival, 39 months; 95% CI, 35 to 77 months; log-rank test, P = .02; hazard ratio = 1.77; 95% CI, 1.09 to 2.86; Fig 1). This difference persisted in a multivariable analysis; women who had a history of HRT use had an adjusted hazard ratio of dying from lung cancer of 1.97 (95% CI, 1.14 to 3.39) compared with women who never used HRT. This seemed to be more pronounced in smokers compared with nonsmokers. Women who smoked and used HRT had a worse overall survival compared with women who smoked, but did not use HRT (median survival, 39 months; 95% CI, 32 to 72 months v 73 months; 95% CI, 64 to 82 months, respectively; P = .03). This difference in survival based on HRT use was not as prominent among nonsmokers. Overall survival was lower in nonsmoking women who used HRT (median survival, 92 months) compared with women who did not use HRT (median survival, 98 months; 95% CI, 86 to 100 months). However, this difference was not statistically significant (P = .4).

    DISCUSSION

    It is well known that sex differences in the incidence and prognosis of lung cancer exist. The exact role of estrogens in the pathogenesis of lung cancer is unclear, but estrogen receptors have been found in normal lung and tumor cell lines and tissues.14, 15 It is believed that estrogen can directly stimulate the transcription of estrogen-responsive genes in the nucleus of pulmonary cells and activate growth factor signaling pathways, in particular the epidermal growth factor pathway, thereby contributing to carcinogenesis in the lung.16 A recent randomized clinical trial comparing the efficacy of the irreversible steroidal aromatase inhibitor exemestane with tamoxifen in decreasing the risk of breast cancer recurrence found that women randomly assigned to tamoxifen had an increased incidence of second primary nonbreast cancers, mainly lung cancer.17 This suggests that the estrogen receptor–agonistic properties of tamoxifen may be responsible for the increased risk of cancer, especially lung cancer.

    In a large population-based study using the Surveillance, Epidemiology, and End Results database, Moore et al18 found that premenopausal women presented more often with advanced clinical stage, less favorable histology (ie, adenocarcinoma), and poorly differentiated tumors compared with postmenopausal women, thereby suggesting that estrogen may contribute to the carcinogenesis of lung cancer. In that study, however, they found that the overall survival was not different in premenopausal women compared with postmenopausal women. The authors concluded that, although exposure to estrogen early in life may initiate lung tumorigenesis, lifelong exposure to estrogen may create a milieu that may confer a protective effect.

    In another retrospective study, Ettinger et al19 compared mortality rates of postmenopausal women using HRT with those of women who had never used HRT or had used it for less than a year. They found that estrogen use was associated with a decreased risk for lung cancer mortality (relative risk = 0.22; 95% CI, 0.04 to 1.15). However, this decrease was not statistically significant. Despite the limitations of our large study, which include its retrospective nature and possible inconsistency between the documented evidence of HRT and the actual use by the patients, we found that use of HRT adversely affected survival in women with lung cancer.

    Another interesting finding in our study was that the effect of HRT was more pronounced in smoking women versus nonsmokers. These results are similar to the results found by Taioli and Wynder,10 who reported a positive interaction between smoking and estrogen replacement therapy and the development of adenocarcinoma of the lung. This suggests a possible interaction between estrogens and the carcinogens present in cigarette smoke. Wei et al20 have suggested that women have lower DNA repair capacity than men, and Nelson et al21 have demonstrated that K-ras mutations are much more common in non–small-cell lung cancers from female smokers than from male smokers. Estrogen could enhance the proliferation of neoplastic cells with these molecular aberrations and increase the risk of developing lung cancer sooner rather than later in smoking women exposed to exogenous estrogen. Another effect of estrogen in influencing lung carcinogenesis may be via gastrin-releasing peptide, which plays a role in neoplasia by stimulating cell proliferation.22, 23 Shriver et al22 reported that increased gastrin-releasing peptide receptor mRNA expression was seen in female smokers compared with female nonsmokers. They also showed an increased expression of the gastrin-releasing peptide receptor gene when human airway cells were exposed to estrogen, suggesting that this gene could also be regulated by the hormone.22

    Another limitation of this study was the lack of information on the exact dose and duration of HRT use in every patient. Also, we did not distinguish between the various estrogens that had been used as part of HRT. Certain other confounding factors, such as age at menopause, age at starting and stopping HRT, and socioeconomic factors, were not available for a large number of patients and, hence, could not be included in the analysis. Although this may have had an effect on the magnitude of the effect seen, we do not believe that it would have altered the nature of the effect observed overall.

    Further studies are needed to confirm our finding because this could have a major impact on the management of menopausal symptoms of women in general and patients with lung cancer in particular. These studies should include a detailed gynecologic history and use of all forms of hormone therapy, including hormonal contraceptives in addition to HRT to obtain a better understanding of the role of estrogens and progestins in the pathogenesis of lung cancer.

    Authors' Disclosures of Potential Conflicts of Interest

    The authors indicated no potential conflicts of interest.

    Author Contributions

    Conception and design: Apar Kishor Ganti, Anil Potti

    Collection and assembly of data: Apar Kishor Ganti, Amit W. Panwalkar, Ketki K. Tendulkar, Anil Potti

    Data analysis and interpretation: Apar Kishor Ganti, Abe E. Sahmoun, Amit W. Panwalkar, Ketki K. Tendulkar, Anil Potti

    Manuscript writing: Apar Kishor Ganti, Abe E. Sahmoun, Anil Potti

    Final approval of manuscript: Apar Kishor Ganti, Abe E. Sahmoun, Amit W. Panwalkar, Ketki K. Tendulkar, Anil Potti

    NOTES

    Presented in part as a poster at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005.

    Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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