Rajaram N, Yap B, Eriksson M, et al. A randomized controlled trial of soy isoflavone intake on mammographic density among Malaysian women. Nutrients. January 2023;15(2):299. doi: 10.3390/nu15020299.
Asian women are experiencing a substantial rise in breast cancer occurrence, which has been attributed to adopting a westernized lifestyle. Breast cancer is the most common cancer in women and one of the leading causes of cancer-related deaths. Ongoing research continues to explore aromatase inhibitors and estrogen receptor modulators as preventative techniques in at-risk populations; however, the benefits of these pharmaceutical interventions may not be worth the risks. Soy (Glycine max, Fabaceae) is a dietary intervention that may help lower risks of breast cancer. Soy-based foods are rich in isoflavones (ISFs), which are phytoestrogens and selective estrogen receptor modulators. Studies of Asian women have demonstrated a 14-41% decreased risk of breast cancer incidence with soy intake. One way to measure breast cancer risk is using mammographic density (MD) as a biomarker. The purpose of this randomized controlled trial was to determine whether soy ISFs used in supplement form or dietary form would impact cancer risk in peri- and postmenopausal Asian women using MD as a biomarker of risk.
Peri- and postmenopausal Asian women were recruited from an established research database of women attending mammography screening from the Subang Jaya Medical Center (Selangor, Malaysia) and the University Malaya Medical Center (Selangor, Malaysia). Social media was used to augment reach. The trial was held between November 2018 and December 2019.
A total of 177 women were recruited. Fifty-nine were excluded for various reasons. The remaining 118 women were randomized to the daily ISF supplement (n = 41), ISF diet (n = 38), or control (n = 39) groups. Thirteen, eight, and six participants were lost to follow up, respectively. One participant in the ISF supplement group was missing primary data; thus, excluded from analysis.
Women in the ISF supplement group were asked to consume two soy ISF tablets once daily (100 mg of soy ISFs; manufacturer not disclosed). Women in the ISF diet arm were instructed to consume two servings of soy foods (50 mg of soy daily). Participants in the ISF arm received a food guide and cash subsidy. Participants in the control arm were asked to continue their regular diet and limit soy-rich foods to a maximum of three servings per week. A food frequency questionnaire (FFQ) was used to assess dietary changes throughout the study period.
Demographic data were collected at baseline, including reproductive factors, physical activity, and medical history. Anthropometric measurements were collected at baseline and the end of the study period. Mammograms were conducted during the screening visit and the end of the study. Average follow-up period was 13.3 months. A total of 91 women completed the study. Twenty-seven were lost to follow-up due to adverse events (n = 13), no longer interested (n = 7), and COVID-19 pandemic (n = 7). Of those, 13 were lost to follow-up in the ISF supplement group, eight in the ISF diet group, and six in the control group. Failure to follow-up did not significantly affect randomization. However, a significant difference was observed in MD percent density (P = 0.03) in those lost to follow-up.
The average age was 57 years, and most study participants were Chinese (78.9%). There were no statistically significant differences in terms of baseline characteristics between the groups. Twelve percent of women reported a first-degree relative with breast cancer. More than half (65.6%) reported their last mammogram was more than two years before beginning the study. Forty-one percent were obese or overweight, and half reported low levels of physical activity. Breast cancer risk factors were distributed equally between the groups. No significant changes in anthropometric were observed following the study.
The ISF diet group reported an increased total calorie intake over the study period, which was attributed to increased protein intake (P = 0.006) and fat intake (P = 0.04). A decrease in total calorie intake was observed in the ISF supplement arm (P = 0.01) attributed to lower protein and fat intake (P = 0.04 and P = 0.02, respectively). No dietary changes were reported in the control group. Expected significant increases in soy isoflavone intake were observed in the ISF supplement and ISF diet groups (P < 0.01 for both). Main sources of soy intake in the ISF diet group included soymilk, soybean curd, and tofu. No other significant findings were observed.
Several sensitivity analyses were conducted including limiting analysis to those more compliant with the intervention, excluding data from women with high isoflavone intake at enrollment, and low MD at enrollment. No differences were detected. Sensitive analysis showed that the greatest absolute decline in MD was observed in women with moderate isoflavone intake (18-61 mg/day) followed by high isoflavone intake (61-101 mg/day). However, little change was observed in women with very high isoflavone intake (> 101 mg/day).
Data stratified by time since menopause showed a large absolute decline in MD for the ISF supplement and ISF diet arms in women with shorter duration since menopause (< 5 years). Women further than five years from menopause showed an increase in MD with very high isoflavone intake. Lack of statistically significant findings were attributed to small sample size.
Adverse events were reported in 62.7% of study participants. Adverse events included gastrointestinal problems, skin rash, joint pains, weight gain, and numbness. Most were observed in the dietary soy group, except joint pain and numbness, which was more common in the ISF supplement group. Serious adverse events included post-menopausal bleeding, two cases of ruptured brain aneurysms, and one breast cancer diagnosis. Several limitations were present, including sample size, poor recruitment, failure to follow-up, moderate soy intake in the control group (18-61 mg/day), self-reporting, and serious adverse events.
Despite the limitations, many of which were exacerbated by the COVID-19 pandemic and national lockdowns, the authors conclude a demonstrative association between soy isoflavone intake and mammographic density changes in Asian women around or soon after menopause. They propose a diet rich in soy isoflavones may be a cost-effective and acceptable primary intervention strategy to reduce breast cancer risk. However, the authors state that the results of this study should be interpreted with caution. Larger trials conducted with Malaysian women are needed to confirm findings.
The authors declare no conflict of interest.