Introduction

Breast cancer is the most common malignancy among women worldwide. Approximately 14% of all female cancer deaths are caused by breast cancer, and it is the second leading cause of cancer-related deaths among women [1]. The estimated age-adjusted incidence rate was 123.8 per 100,000 women per year, and the death rate was 22.6 per 100,000 women per year in 2006-2010 based on data from 18 SEER registries in the USA [2]. In China, the incidence of breast cancer was 21.21 per 100,000 and the mortality rate was 5.13 per 100,000 based on data from 104 cancer registries covering 85 million people in 2009 [3].

Women with breast cancer, particularly those who are younger, commonly experience menopausal symptoms after initial cancer treatment [4–6], including vasomotor (hot flashes and night sweats), atrophic (vaginal dryness), psychological (mood swings), cognitive (fatigue, sleep problems), and somatic (body pain) symptoms due to sudden estrogen withdrawal with the use of chemotherapy and anti-estrogenic treatments, such as tamoxifen [6,7]. In Western countries, most women experience hot flashes with natural menopause [8,9], and as many as 65%-78% of breast cancer patients experience menopausal symptoms after diagnosis and treatment [5,10,11]. Among women living in southeast Asia, it was reported that only about 10%-20% of women report experiencing hot flashes or having psychological complaints during natural transitions to menopause [12]. It has been suggested that this difference may be a result of higher soy food or soy isoflavone consumption among Asian women [13,14]. On the other hand, Asian-American women who experienced natural menopause have reported a high prevalence of vasomotor symptoms (up to 47% for hot flashes and 32% for sweating) [14]. In a recent study, we found a high prevalence of menopausal symptoms (56%-63%), primarily hot flashes and night sweats, among women in China treated for breast cancer, particularly among those who consumed high amounts of soy food [4,15].

Menopausal symptoms have serious effects on women’s quality of life, and medical intervention may be required to alleviate them [9]. This is particularly true for breast cancer patients because of the sudden and severe occurrence of such symptoms at the onset of cancer treatment, especially during chemotherapy and tamoxifen therapy [16–18]. It is generally accepted that estrogen plays a major role in breast cancer development and progression [19,20], suggesting that breast cancer patients with menopausal symptoms could have a better prognosis than those without menopausal symptoms [21] because of estrogen deprivation [22,23]. Mortimer et al. examined the association between the prevalence of menopausal symptoms with disease outcomes among women treated for breast cancer in the Women’s Healthy Eating and Living (WHEL) study in the US and found that women with hot flashes at baseline were less likely to develop disease progression, independent of age, tumor stage, and hormone receptor status, than those without symptoms [21]. To date, no study has investigated the potential role of menopausal symptoms as an indicator of breast cancer prognosis in Asian populations. In the present study, we examined the association of menopausal symptoms experienced by breast cancer patients with disease-specific outcomes such as recurrence in the Shanghai Breast Cancer Survival Study (SBCSS).

Methods

Results

During a median follow-up time of 5.3 years, 676 total deaths and 720 recurrences were reported. About 56% of all patients reported one or more menopausal symptom at baseline. Prevalence for hot flashes was 44.2%, for night sweats was 35.4%, and for vaginal dryness was 8.8%. Among patients with TNM 0-I breast cancer: 808 had hot flashes, 611 had night sweats, and 165 had vaginal dryness; among patients with TNM II breast cancer: 1058 had hot flashes, 870 had night sweats, and 205 had vaginal dryness; and among patients with TNM III breast cancer: 188 had hot flashes, 153 had night sweats, and 36 had vaginal dryness. Demographic, clinical, and lifestyle characteristics in relation to the presence or absence of any of the three major menopausal symptoms are presented in Table 1. The mean (SD) age of women at breast cancer diagnosis was 53.3 (10.1) years; 241 (5.0%) women were less than 40 years old, 1980 (40.9%) aged 40-50 years, 1383 (28.6%) aged 50-60 years, and 1238 (25.5%) aged more than 60 years. Patients who were younger at diagnosis, had a middle and high school education, had fewer pregnancies, were married, were premenopausal, were lean according to BMI and WHR, had no history of chronic disease, had higher daily soy-isoflavone intake, had poor quality of life, received chemotherapy and/or immunotherapy, used tamoxifen, or had positive ER/PR status were more likely to experience menopausal symptoms (P <0.05 for all). Menopausal symptoms did not appear to vary by level of regular exercise, vitamin supplement use, drinking tea or alcohol, cigarette smoking, surgical treatment or radiotherapy, disease stage (TNM stage), or family history of breast cancer.

Associations of breast cancer recurrence with menopausal symptoms according to menopausal status are presented in Table 2. Premenopausal women who experienced hot flashes had a significantly lower risk of recurrence than those who did not have the symptom (HR=0.77, 95% CI: 0.62-0.96). Similarly, lower risk of recurrence was observed as the number of menopausal symptoms experienced increased among premenopausal women (HR= 0.73, 95% CI: 0.56-0.96 for experiencing ≥2 symptoms vs. for women without symptoms). No significant associations were found among postmenopausal women. Tests for multiplicative interaction between menopausal symptoms and menopausal status with recurrence risk, however, were not significant (P interactions >0.05 for all). Kaplan-Meier Curves describing the association of hot flashes and number of menopausal symptoms with recurrence is shown in Figures 1 and 2.

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Figure 1. Hot flashes in association with breast cancer recurrence, SBCSS.

https://doi.org/10.1371/journal.pone.0075926.g001

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Figure 2. Number of menopausal symptoms in association with breast cancer recurrence, SBCSS.

https://doi.org/10.1371/journal.pone.0075926.g002

The joint effects of menopausal symptoms, BMI, and WHR on breast cancer recurrence are presented in Tables 3 and 4. We found that experiencing hot flashes was associated with a lower risk of recurrence among women with low BMI (HR= 0.78, 95% CI: 0.64-0.99) or low WHR (HR= 0.77, 95% CI: 0.61-0.97) compared with those without hot flashes and with high BMI (≥25.0) or with high WHR (≥0.832). However, test for multiplicative interaction was only significant for WHR (P-interaction=0.05), but not for BMI (P-interaction=0.24). Similarly, experiencing ≥2 menopausal symptoms was associated with a lower risk of recurrence among women with low BMI (HR= 0.81, 95% CI: 0.62-1.05) or low WHR (HR= 0.71, 95% CI: 0.53-0.95), but not among women with high body or abdominal fatness and without menopausal symptoms. Interaction tests between the number of menopausal symptoms and BMI or WHR were not statistically significant (P-interaction=0.51 and 0.13, respectively).

We also examined joint associations between menopausal symptoms and tamoxifen use or soy-isoflavone intake and breast cancer recurrence (Tables 5 and 6). Tamoxifen users with hot flashes had a significantly lower risk of recurrence (HR= 0.75, 95% CI: 0.58-0.98) than those who did not use tamoxifen and reported no hot flashes. However, the interaction test across these subgroups was not significant (P-interaction=0.30). Similarly, patients who experienced ≥2 menopausal symptoms and used tamoxifen had a lower risk of recurrence (HR=0.71, 95% CI: 0.52-0.96) than those with no tamoxifen use and no menopausal symptoms. Associations between menopausal symptoms and breast cancer recurrence did not differ by soy-isoflavone intake.

Discussion

In this large population-based cohort study of 4,842 breast cancer patients aged 20-75 years, experiencing menopausal symptoms, especially hot flashes, as well as experiencing multiple symptoms during the first 6 months post-diagnosis, were associated with a lower risk of recurrence. These associations were predominantly seen among premenopausal women, women with low BMI or WHR, and those who used tamoxifen. To our knowledge, this study is the first large-scale, prospective investigation to provide evidence for an inverse association between menopausal symptoms, particularly hot flashes, shortly after breast cancer diagnosis and during the initial cancer treatment period, and breast cancer recurrence in Chinese women. Vaginal dryness and night sweats were less common among our study participants and were not associated with recurrence risk in our population, as has been previously reported for women in North America [23].

Although the biological mechanisms underlying vasomotor symptoms such as hot flashes and night sweats are not very clear, it has been reported that these symptoms may be related to the acute drop in estrogen levels during natural and medically induced menopause [22,29]. Women of reproductive age or premenopausal women usually do not experience these symptoms [9]. However, premenopausal women with breast cancer experience frequent and severe vasomotor symptoms as a result of chemotherapy and tamoxifen therapy [5,16,23]. Thus, having vasomotor symptoms following treatment for breast cancer may indicate estrogen deprivation or decreased levels of circulating estrogen, suggesting treatment efficacy [21,30]. This hypothesis is supported by our current findings that premenopausal women who experienced hot flashes following cancer treatment had a lower risk of breast cancer recurrence.

Tamoxifen is one of the most widely used drugs for breast cancer patients [31,32] and effectively reduces death and recurrence from breast cancer. Tamoxifen and its metabolites, particularly 4-hydroxy-tamoxifen (4-HO tamoxifen) and 4-hydroxy-N-desmethyl tamoxifen (endoxifen), have potent anticancer effects, because of their anti-estrogenic properties [31]. In the WHEL study, among 864 tamoxifen-using patients (aged 18-70 years) with Stage I-IIIa breast cancer, those who experienced hot flashes during the first 2-48 months after cancer treatment were less likely to develop recurrent breast cancer after 7.3 years than those who did not experience this symptom (12.9% vs. 21%, P=0.01) [21]. The authors conclude that hot flashes are a strong predictor of breast cancer-specific outcomes [21]. Consistent with the WHEL finding, we found that women treated with tamoxifen had a lower risk of recurrence only if they experienced hot flashes. It is likely that this group of women may have experienced very low estrogen levels and, thus, had more serious symptoms. Unfortunately, we did not collect information on the severity of symptoms, nor did we measure estrogen levels.

We also observed that patients with lower BMI or WHR had a lower risk of recurrence, if they had hot flashes or reported multiple symptoms. Higher BMI and WHR, indicators for overall and central obesity, have been associated with high circulating estrogen levels [33,34], which, in turn, have been implicated in breast cancer development and progression [35,36]. Women with low BMI or WHR, particularly those with menopausal symptoms, are likely to have lower estrogen or insulin levels, which could translate into lower risk for breast cancer recurrence and better prognosis.

Soy-isoflavone is known to have anti-estrogenic properties [37]. The association between soy food intake and menopausal symptoms among breast cancer patients has been described in detail in another publication, in which we found that women in the highest quartile of soy food intake were 159% more likely to experience hot flash than those in the lowest quartile of soy food intake at 36 months postdiagnosis [15]. Thus, breast cancer patients with high soy food consumption may have a lower level of estrogen exposure. We evaluated the interaction between soy food intake and menopausal symptoms in relation to breast cancer recurrence and found no evidence of interaction.

Menopausal symptoms are known to negatively affect women’s quality of life (QoL), including breast cancer survivors [38–40]. Our finding that experiencing menopausal symptoms was associated with a favorable outcome highlights the potential risk of alleviating menopausal symptoms by increasing estrogen level among breast cancer patients. More research on alternative, non-estrogen related approaches for reducing menopausal symptoms among breast cancer survivors are warranted.

Several potential limitations should be considered in this study. First, data on menopausal symptoms were collected through in-person interviews by self-reports. Some Chinese women may not report certain symptoms, such as vaginal dryness, considering it too private. Thus, misreporting and under-reporting are likely, which would have biased our results towards null. Second, we did not collect information on the severity, frequency, or duration of symptoms. Third, although the results were adjusted for a wide range of covariates, the possibility of residual confounding still exists. Fourth, the lack of direct measurement of estrogen hormone levels prevented us from investigating the underlying mechanisms for the associations between menopausal symptoms and breast cancer recurrence. Our study also has several strengths. This is a large, population-based, prospective study specifically designed to investigate the association of menopausal symptoms with breast cancer recurrence among Chinese women. The high response rates, as well as the detailed information on socio-demographic, anthropometric, clinical, and lifestyle characteristics, collected using a well-validated questionnaire, minimized selection bias and allowed us to account for confounding from multiple factors and to evaluate potential interactions.

In summary, we found that the occurrence of menopausal symptoms, including hot flashes, night sweats, and/or vaginal dryness during the first 6 months post-diagnosis and post- treatment, were associated with a lower risk of breast cancer recurrence among Chinese women. Although experience of menopausal symptoms is a subjective feeling from patients, the link between low estrogen exposure and menopausal symptoms has been well established [15]. Thus, experiencing hot flashes or multiple menopausal symptoms may be a clinically relevant predictor of better breast cancer outcomes, particularly for premenopausal women, tamoxifen users, and those with low body fatness when direct measurement of estrogen level is not available. Further research is needed to examine the relationship between the severity, frequency, and duration of menopausal symptoms and breast cancer outcomes, while accounting for other estrogen-related factors.

Acknowledgments

We are grateful to the research staff of the Shanghai Breast Cancer Survival Study in Shanghai, China for implementing the study and to all of the women who participated in the SBCSS. We also thank Dr. Fan Jin for her contributions to the field operations and Ms. Bethanie Rammer and Mrs. Jacqueline Stern for editorial and technical assistance in the preparation of the manuscript.