Hormone Replacement Therapy and Decreased Lung Cancer Survival

In this issue of Journal of Clinical Oncology, Ganti et al describe the results of a study using retrospective chart review to investigate hormone replacement therapy (HRT) use by women diagnosed with lung cancer. The data, collected on almost 500 female lung cancer patients, showed a significant association between both a lower median age at lung cancer diagnosis (63 v 68 years) and a shorter median survival time (39 v 79 months) in women who used HRT for at least a 6-week period before diagnosis, compared with women who did not. Both observations were highly significant, and the effect on survival persisted in a multivariate analysis. In this analysis, HRT use was associated with an adjusted hazard ratio of dying as a result of lung cancer of 1.97. HRT use was considered positive whether it occurred immediately before diagnosis or was remote from diagnosis, as long as hormone replacement was documented for at least 6 weeks. Given that younger lung cancer patients, as a group, have better survival times than older patients, this degree of effect of HRT on poor outcome in a generally younger population is particularly striking. The effect on poor survival remained statistically significant in women with a smoking history of at least five packyears, who made up 86% of the cohort, whereas the difference in survival between the nonsmoking group (14% of patients) who did or did not use HRT was much smaller (median survival, 92 v 98 months), and was not significant. Stage distribution was not different between users and nonusers of HRT, suggesting the effect was not due to differences in time from symptoms to diagnosis between the two groups, nor to a greater dissemination of disease in HRT users relative to nonusers at the time of diagnosis. Distribution of different lung cancer histologies also was the same regardless of HRT status. The shift to both an earlier age at diagnosis and to shorter survival times with HRT use is consistent with a tumor-promoting effect of HRT. This might occur by accelerating the transition of a preneoplastic lesion to a fully malignant state (hence reducing age at diagnosis) or by promoting a more aggressive behavior of the tumor once it is clinically apparent (hence decreasing survival time). Estrogens in HRT are the most likely candidates for mediating such effects, considering recent evidence showing expression of estrogen receptors (ERs) and growth-promoting effects of estrogens in lung tumors. The ER in particular is highly expressed in most types of lung cancer and mediates transcriptional responses in lung cancer cells. Cross activation of the ER and epidermal growth factor receptor pathways also has been shown to occur in lung cancer cells. Progesterones, which are also often a component of HRT, may actually protect against lung cancer. A recent report suggests that progesterone receptors are present in about half of lung tumors, and progesterone mediates pathways that induce apoptosis in lung cancer cells and reduce lung tumor growth. Depending on the hormonal components of HRT and the expression of ER and progesterone receptor in a particular patient’s tumor, either growth-promoting or growth-inhibiting effects might dominate. The study by Ganti et al does have several limitations. The retrospective nature of the study did not allow the investigators to distinguish the type of HRT used or the total duration of HRT use. The continued HRT use after diagnosis of lung cancer is also unknown, but because there has been no contraindication for HRT use after a lung cancer diagnosis, the authors presumed HRT use was probably not curtailed. However, a dose-response analysis could not be carried out. Given that nonsmokers made up such a small group of the patients studied, only a trend was discerned for reduced survival with HRT use. The promoting effects of HRT on lung cancer found by Ganti et al also are not consistent with recent data by Schabath et al suggesting that HRT use could actually protect women from a lung cancer diagnosis, especially if they smoked. The reduced odds ratio for lung cancer found by Schabath et al in smoking HRT users might be explained by effects of HRT to reduce other cancerpromoting hormones, such as insulin-like growth factor 1, or by the cancer-protecting effects of progesterone described above. Another explanation is that the ER, when it is in the activated state bound to estrogen, can complex with the aryl hydrocarbon receptor, only if it is activated by xenobiotics such as polycyclic aromatic hydrocarbons found in tobacco smoke. The activated ER–aryl hydrocarbon receptor complex is subject to rapid proteosomal degradation, thus eliminating ER signaling. This could paradoxically reduce estrogen signaling in postmenopausal women who took HRT and smoked, providing the appearance of a protective effect of HRT on lung cancer risk. In the case-case analysis carried out by Ganti et al, women who were not diagnosed with lung cancer are not considered. It may be that HRT use combined with tobacco smoke exposure can inhibit growth-promoting processes in some women. In others, however, the promotional effects of HRT may dominate to produce lung tumors that are diagnosed earlier in life and are more biologically aggressive and resistant to therapy. HRT use of relatively short duration might also JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 24 NUMBER 1 JANUARY 1 2006