Hormone Therapy and Risk of Lung Cancer

Abstract & commentary

By Jeffrey T. Jensen, MD, MPH, Editor, Leon Speroff, Professor of Obstetrics and Gynecology, Vice Chair for Research, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.

Synopsis: An increase in the risk of lung cancer diagnosis was seen in users of combined estrogen-progestogen hormone replacement therapy. The risk increased with duration of use, and became significant after 10 years of exposure. The association was not seen with estrogen-only therapy.

Source: Slatore CG, et al. Lung cancer and hormone replacement therapy: Association in the vitamins and lifestyle study. J Clin Oncol 2010;28:1540-1546.

Lung cancer is the leading cause of cancer-related mortality among women. To investigate the potential role of hormone replacement therapy (HRT) in lung cancer development, the authors evaluated a prospective cohort of 36,588 peri- and postmenopausal women aged 50-76 years from Washington State recruited in 2000-2002 as part of the Vitamins and Lifestyle (VITAL) Study. The cohort was established from a mailing to 168,953 women aged 50-76 years who lived in the area covered by the Seattle-Puget Sound Surveillance, Epidemiology, and End Results (SEER) registry. After exclusion for a variety of factors, the subjects tended to be more educated and less likely to be current smokers, but were similar in body mass index (BMI) to the general population. Deaths were ascertained by linkage to Washington State death files, and moves out of the area from the National Change of Address System. Participants with a previous diagnosis of lung cancer, or those with lung cancer identified only on a death certificate were excluded. Only perimenopausal (defined as having menses in the past year that were not regular) and postmenopausal (defined as no periods in the year before baseline, ever use of HRT, bilateral oophorectomy, or age ≥ 60 years) were studied. Exposure to HRT was obtained by self report and categorized by use status (never, former, current) and years of use (< 1, 1-4, 5-9, 10-14, or ≥ 15 years). Years of estrogen plus progestin (EP) use and years of estrogen-only use were computed separately. The reference group was users of neither type of HRT. The outcome, lung cancer, was identified through the SEER cancer registry during 6 years of follow-up. Hazard ratios (HRs) associated with use and duration of specific HRT formulations were calculated for total incident lung cancer, specific morphologies, and cancer by stage at diagnosis.

A total of 344 cases of lung cancer were identified. After adjusting for smoking, age, and other potential confounders, there was an increased risk of incident lung cancer associated with increasing duration of combined EP use (HR, 1.27; 95% confidence interval [CI], 0.91-1.78 for 1-9 years; and HR, 1.48; 95% CI, 1.03-2.12 for ≥ 10 years; P for trend = 0.03). There was also a significant trend toward a more advanced stage at diagnosis associated with increasing exposure to EP therapy. In contrast, use of unopposed estrogen was not associated with an increased risk of lung cancer diagnosis.

The authors concluded that use of combined HRT increases the risk of developing lung cancer in a duration-dependent manner, with an approximate 50% increased risk for use of 10 years or longer.

Commentary

I had planned to write this month about the North American Menopause Society's (NAMS) 2010 Position statement on estrogen and progestogen use in postmenopausal women.1 The revised NAMS statement does not contain any new information or surprises for careful readers of OB/GYN Clinical Alert, but nonetheless these public statements are welcome. Controversy and confusion remains prevalent in many published guidelines for postmenopausal HRT, most of which reflect an undue influence of the Women's Health Initiative initial reports. This has led to an overly conservative approach to therapy by many providers. Consequently, large numbers of postmenopausal women do not receive adequate counseling on the benefits and risks of HRT from their providers, while others are misinformed by overly pessimistic reports in the media.

The North American Menopause Society is a nonprofit scientific organization dedicated to the advancement of women's health through the study of menopause. NAMS published an initial position statement on the role of menopausal HRT in October 2002 in response to the first WHI report, and has issued updated statements in September 2003, October 2004, March 2007, and July 2008 to clarify the benefit-risk ratio of HRT for both treatment of menopause-related symptoms and disease prevention at various times through menopause and beyond. The current report provided updates to all the existing sections, and added new information on ovarian and lung cancer.

The 2010 statement reiterated the previous position that estrogen therapy (ET) is the most effective treatment for vasomotor symptoms, and for moderate-to-severe vulvar or vaginal atrophy. The major proven systemic benefit of HRT is a reduction in fracture risk (principally hip fracture). Cardiovascular disease is the No. 1 killer of postmenopausal women. The 2010 Position Statement recognizes that the primary difference between observational studies (that show a benefit of systemic HRT in reducing the risk of CHD) and RCTs (that show no benefit or harm) is timing of initiation of therapy. In general, starting HRT before age 55 or within 5 years of onset of menopause is associated with benefit, while later initiation is associated with increasing risk. The principle risk of HRT is the alteration in hepatic globulins that increases blood clotting. This manifests as a small increase in the risk of ischemic stroke (but no difference in hemorrhagic stroke), and an approximately 2-fold increase in risk of venous thromboembolism (VTE) that is observed across both observational and randomized studies using oral estrogen. More recent evidence from case-control studies suggests that the increase in risk of VTE is observed with oral administration, but not transdermal delivery of estradiol.2 In addition, the important interaction of obesity with VTE risk (3-fold increase) has recently become more widely recognized.3

However, in the office, many discussions of HRT center almost exclusively on cancer risk. A growing body of evidence suggests that HRT may promote the growth of pre-existing breast cancers, with small increases in the risk of breast cancer diagnosis seen in the WHI study among women using combined HRT, but no increase in risk in women using conjugated estrogens alone.4 A small increase in the risk of ovarian and lung cancer has also been observed. The lung cancer issue is the newest and most important data, as lung cancer is the No. 1 cause of cancer death in women.

The present report by Slatore et al has the standard biases of database studies. It relies heavily on self-report of exposure, and is not representative of the true population with respect to smoking history. Women using estrogen-only therapy were significantly younger and more likely to have undergone hysterectomy with removal of both ovaries. Nonetheless, the association with combined HRT (but not E alone) and breast cancer actually strengthened with adjustment for potential confounders such as smoking and BMI, and the HR increased with duration of use.

To put this into perspective, we need to consider consistency of effect, biologic plausibility, and absolute risk. A similar magnitude of risk for lung cancer was observed for EP therapy in the randomized Heart and Estrogen/Progestin Replacement Study (HERS) trial, although the finding was not statistically significant (HR, 1.39; 95% CI, 0.84-2.28).5 The same nonsignificant increase was observed in the WHI (HR, 1.23; 95% CI, 0.92-1.63).6

The incidence of lung cancer is higher among women than men, suggesting an important gender difference that hints to biologic plausibility.7 Both estrogen receptors and aromatase, the enzyme that synthesizes 17β-estradiol (E2), are expressed by lung tumors, suggesting a role for female steroid hormones in lung cancer growth.8 A number of basic research and clinical studies support a role for local production of estrogen and expression of ERs in lung tumors that arise in men as well as in women. GPR30, a novel protein expressed in lung tumors at high levels, binds E2 and may be a proliferation factor.8 Still, if estrogen is the whole story, why is the increase in lung cancer not observed in women using unopposed estrogen?

So how do we counsel our patients? This leads us to the discussion of absolute risk. In the United States lung cancer deaths in women now surpass those caused by breast, ovarian, and cervical cancers combined.9 However, the incidence of lung cancer in nonsmoking women is only about 15-20/100,000 person-years for women ages 40-79 years. For female smokers this increases to between 149-263/100,000 person-years. Assuming a 48% increase in risk with EP therapy, this would translate to an additional 7-9 cases of lung cancer per 100,000 nonsmokers, and 70-120 cases among smokers. Thus, for nonsmokers the number of lung cancer cases attributable to HRT is negligible, while for smokers the risk is similar in magnitude to that observed for breast cancer among EP users (approximately 8-11 additional cancers diagnosed). However, it is important to keep in mind that the survival for women with lung cancer is much lower than with breast cancer.

Taken together, the powerful increase in lung cancer risk attributable to smoking outweighs any other factor, and we should redouble our efforts to help our patients quit. While female smokers are at an increase risk of lung cancer, and combined HRT appears to significantly magnify the risk, women who smoke are also at higher risk for osteoporosis and fracture. A thorough discussion of risks and benefits needs to occur and should address all of these competing interests. Clinicians should document in the medical record the discussion of lung cancer risk and HRT in a similar way they describe breast cancer risk. As noted in the NAMS position paper, for most healthy recently menopausal women, the benefits of HRT will outweigh the risks.

References

  1. Estrogen and progestogen use in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause 2010;17:242-255.
  2. Canonico M, et al. Hormone therapy and venous thromboembolism among postmenopausal women: Impact of the route of estrogen administration and progestogens: The ESTHER study. Circulation 2007;115:840-845.
  3. Canonico M, et al. Obesity and risk of venous thromboembolism among postmenopausal women: Differential impact of hormone therapy by route of estrogen administration. The ESTHER Study. J Thromb Haemost 2006;4:1259-1265.
  4. Fournier A. Should transdermal rather than oral estrogens be used in menopausal hormone therapy? A review. Menopause Int 2010;16:23-32.
  5. Hulley S, et al. Noncardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002;288:58-66.
  6. Chlebowski RT, 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.
  7. Wakelee HA, et al. Lung cancer incidence in never smokers. J Clin Oncol 2007;25:472-478.
  8. Siegfried JM, et al. Estrogen receptor signaling in lung cancer. Semin Oncol 2009;36:524-531.
  9. Horner MJ, et al, eds. SEER Cancer Statistics Review, 1975-2006, National Cancer Institute. Bethesda, MD: 2009. Available at: http://seer.cancer.gov/csr/1975_2006/. Based on November 2008 SEER data submission, posted to the SEER web site, 2009.