Soy Food Intake and Risk of Lung Cancer

Evidence From the Shanghai Women's Health Study and a Meta-Analysis

Gong Yang; Xiao Ou Shu; Wong-Ho Chow; Xianglan Zhang; Hong-Lan Li; Bu-Tian Ji; Hui Cai; Shenghui Wu; Yu-Tang Gao; Wei Zheng

Disclosures

Am J Epidemiol. 2012;176(10):846-855. 

In This Article

Discussion

Concerns about the adverse effects of hormone therapy have led to increased interest in naturally occurring plant-based estrogens,[7,49] especially soy phytoestrogens, as alternative approaches to optimize postmenopausal health.[10,50] In this large, population-based, prospective cohort study of women, 97.2% of whom were never smokers, we found that increasing intake of soy foods was associated with a substantially reduced risk of lung cancer. This association was independent of traditional risk factors for lung cancer and was not explained by differences in consumption of other dietary components, such as fruits and vegetables.

In this study, we found that the soy–lung cancer association varied significantly by tumor behavior; the inverse association with soy food intake was more pronounced for aggressive lung cancer, a form of lung cancer that generally has a short survival time. This finding is in direct contrast to the Women's Health Initiative finding of a more significantly increased risk of aggressive lung cancer with use of combined hormone therapy.[7] Emerging evidence suggests that estrogen signaling promotes lung cancer proliferation and progression,[5–8] and as mentioned above, estrogen receptor antagonists such as tamoxifen may counteract the detrimental effect of hormone therapy on lung cancer.[5,8] Soy phytoestrogens have been shown to act as natural estrogen antagonists and have diverse cancer-inhibitory activity, including induction of apoptosis and cell-cycle arrest and inhibition of tumor invasion and angiogenesis.[17–20,22] This novel finding of a protective effect of soy foods against aggressive lung cancer merits further investigation, particularly among users of hormone therapy.

Another novel finding from this study is that the soy–lung cancer association may be modified by endogenous estrogens. Soy isoflavones have a diphenolic structure similar to that of 17β-estradiol and can compete with endogenous estrogens in the binding of estrogen receptors.[11] The biologic behavior of isoflavones may thus be modulated by individuals' endogenous estrogen levels. It has been shown that isoflavones act primarily as estrogen agonists in a low-estrogen environment, whereas they act like estrogen antagonists in a high-estrogen environment.[51] Our finding of an inverse association of soy consumption with lung cancer risk was predominantly observed among women with indicators of longer and higher exposure to endogenous hormones, which suggests that the effect of soy on lung cancer may, at least in part, be due to its estrogen antagonist-like effect. However, we did not find that risk estimates associated with isoflavone intake were stronger than risk estimates associated with soy food intake. This may be because measurement errors in the assessment of isoflavone intake are larger than measurement errors related to soy food intake.[52] On the other hand, soy foods are also rich in calcium, folic acid, and fiber and contributed 26%, 18%, and 15% of the total intake of these nutrients, respectively, in this study population. It is possible that these and probably many other phytochemicals found in soy foods are also responsible for the observed cancer-preventive effect of soy foods.

The observed inverse association between soy food intake and lung cancer risk in the SWHS was further supported by our meta-analysis of 7 studies that had specifically estimated lung cancer risk for nonsmokers (6 published studies plus the present study),[39–48] with a summary relative risk of 0.59 (95% CI: 0.49, 0.71). Results from previous cohort studies carried out among nonsmokers have been rather consistent,[46,47] although heterogeneity in the association is present across studies of smokers (Table 5). In 2 Asian cohort studies,[46,47] isoflavone intake was found to be inversely associated with lung cancer risk in both male[46] and female[47] lifetime nonsmokers but not in current or former cigarette smokers. A similar but statistically nonsignificant protective effect of isoflavones was also suggested in the Iowa Women's Health Study.[48] However, that study, like other studies of soy/isoflavones and health outcomes conducted in Western populations, was limited by the generally very low intake of isoflavones (median intake was 0.25 mg/day, as compared with 27.9 mg/day in our study population).

Several features distinguish this study from previous investigations. This study population was well suited to examination of the soy–lung cancer association given its high yet diverse soy food intakes. The median intakes of isoflavones for the highest and lowest quintile categories (58.6 mg/day vs. 12.2 mg/day) varied nearly 5-fold. Particularly noteworthy characteristics of this cohort are the extremely low prevalences of use of tobacco products (2.8%) and hormone therapy (2.0%; users of hormone therapy were excluded from the analysis); thus, the potential for effect masking by cigarette smoking or confounding by postmenopausal hormone use should have been minimal. Other strengths of our study include a prospective design, high rates of participation (93% at enrollment) and follow-up (over 96% for active, in-person follow-up), use of repeated dietary assessments with a validated FFQ, and use of an in-person interview.

As with all nutritional epidemiology studies, measurement error in assessing soy food intake is a possible concern, although the FFQ used in this study had been previously evaluated and found to have reasonably good validity for the measurement of usual dietary intake of soy foods.[28] The validity of the FFQ for assessing soy food intake is also supported by our recent work showing moderate correlation (r = 0.48) between soy food intake derived from the FFQ and the mean level of isoflavone excretion measured in 4 spot urine samples collected quarterly over a 1-year period.[53] In addition, the inverse association was consistently observed for all of the analytic approaches used in the study, including the analysis of baseline FFQ data alone, the cumulative average of the baseline and second FFQs, and the 7-day dietary recall administered at baseline. Furthermore, because the exposure assessment was conducted prospectively and prior to cancer diagnosis, errors in measurement of soy consumption are likely to have been nondifferential, which would have tended to attenuate the true association between soy consumption and lung cancer. Another concern is that we could not completely rule out the possibility of residual confounding due to unmeasured or inaccurately measured covariates, although we carefully adjusted for a wide range of dietary and nondietary factors that are potential confounders of the soy–lung cancer association.

The direction and magnitude of risk estimates for lung cancer associated with soy food intake in this study were generally similar to risk estimates in our meta-analysis of previous studies. Therefore, although our study was conducted in a relatively homogeneous population (Chinese women with very low prevalences of tobacco-product and postmenopausal hormone use), the present findings should have wider relevance.

In conclusion, this prospective cohort study, reinforced by a meta-analysis, provides strong evidence that soy food consumption may confer protection against lung cancer, particularly aggressive lung cancer, among nonsmoking women. Given the fact that incidence of lung cancer among women is increasing steadily worldwide and that soy can be readily incorporated into most diets, our findings, if replicated in other populations, would have important public health implications for the prevention of this common, fatal malignancy.

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