Abstract
PURPOSE
This project examined the association between dietary intake of soy or cruciferous vegetables and breast cancer treatment-related symptoms among Chinese-American (CA) and Non-Hispanic White (NHW) breast cancer survivors.
METHODS
This cross-sectional study included 192 CA and 173 NHW female breast cancer survivors (stages 0–III, diagnosed between 2006–2012) recruited from two California cancer registries, who had completed primary treatment. Patient-reported data on treatment-related symptoms and potential covariates were collected via telephone interviews. Dietary data were ascertained by mailed questionnaires. The outcomes evaluated were menopausal symptoms (hot flashes, night sweats, vaginal dryness, vaginal discharge), joint problems, fatigue, hair thinning/loss and memory problems. Associations between soy and cruciferous vegetables and symptoms were assessed using logistic regression. Analyses were further stratified by race/ethnicity and endocrine therapy usage (non-user, tamoxifen, aromatase inhibitors).
RESULTS
Soy food and cruciferous vegetable intake ranged from no intake to 431 and 865 grams/day, respectively, and was higher in CA survivors. Higher soy food intake was associated with lower odds of menopausal symptoms (≥ 24.0 versus 0 grams/day, OR=0.51, 95% CI: 0.25, 1.03), and fatigue (≥ 24.0 versus 0 grams/day, OR=0.43, 95% CI: 0.22, 0.84). However, when stratified by race/ethnicity, associations were statistically significant in NHW survivors only. Compared with low intake, higher cruciferous vegetable intake was associated with lower odds of experiencing menopausal symptoms (≥70.8 versus <33.0 grams/day, OR=0.50, 95% CI: 0.25, 0.97) in the overall population.
CONCLUSIONS
In this population of breast cancer survivors, higher soy and cruciferous vegetable intake was associated with less treatment-related menopausal symptoms and fatigue.
Keywords: Cruciferous Vegetables, Soy Foods, Breast Cancer Survivors, Endocrine Therapy, Late Treatment Effects
Introduction
Breast cancer survivors often experience late effects, defined as cancer or cancer treatment-related health problems occurring months or years after diagnosis or completion of treatment [1,2]. Endocrine therapy (ET) after primary treatment may further contribute to treatment-related symptoms [3,4]. Commonly reported late effects and side effects of ongoing endocrine therapy, include menopausal symptoms (e.g. hot flashes, night sweats), fatigue, cognitive changes (e.g. difficulty concentrating and memory loss), and hair thinning/loss [3–8]. Treatment-related symptoms impact the quality of life in breast cancer survivors [9,10], fostering interest in identifying approaches to ameliorate side/late effects.
Phytochemicals (boactive food components), such as isoflavones in soy and glucosinolates in cruciferous vegetables (e.g. cauliflower, cabbage, bok choy, turnip and mustard greens and broccoli), may be dietary factors with the potential to influence late/side effects. Isoflavones bind to estrogen receptors and exert weak estrogenic effects [11,12], possibly reducing menopausal symptoms and other treatment-related symptoms. Some evidence supports an inverse association between soy isoflavones and menopause-associated vasomotor symptoms (hot flashes, night sweats) in women without cancer [13–15], but in breast cancer survivors, data is limited and inconsistent [16–20]. To our knowledge, no prior studies have investigated the relationship between soy intake and other treatment-related symptoms (e.g. joint pain, fatigue, memory loss). Cruciferous vegetables contain many bioactive components, such as glucosinolates [21], and to our knowledge, no previous studies have investigated the relationship between cruciferous vegetables and breast cancer treatment-related symptoms. However, possible mechanisms exist through which cruciferous vegetable intake may impact treatment-related symptoms, including reducing of inflammation and influencing levels of several phase I (cytochrome P450 1A1) and phase II (glutathione S-transferase) metabolism enzymes, which mediate, among other compounds, levels of estrogen and estrogen-related metabolites [22–27].
Identification of lifestyle factors associated with breast cancer treatment-related effects is essential as they may be used to reduce symptoms. In this study, we examined the association between intakes of soy products, cruciferous vegetables, and major active compounds in these foods, isoflavones and glucosinolates, with common breast cancer treatment-related symptoms (menopausal symptoms, fatigue, joint problems, hair thinning/loss, and memory loss) among Chinese-American (CA) and Non-Hispanic White (NHW) breast cancer survivors.
Methods
Study Population
This study utilized cross-sectional survey data collected as part of a cross-cultural research project on breast cancer survivorship among Chinese-American (CA) and Non-Hispanic White (NHW) living in California, USA. Women diagnosed with breast cancer between May 2006 and January 2012 were recruited from the U.S. National Cancer Institute’s Surveillance, Epidemiology and End Results Program (SEER) cancer registries in the Greater Bay and Los Angeles areas. Potential participants were randomly selected and sent an invitation letter, a brochure summarizing study objectives and procedures, and an opt-out form with a pre-stamped envelope. Those who did not mail back the opt-out form two weeks after our mailing were contacted by phone. Among 1,910 mailed letters, 61.3% (N=1,171) of patients either returned the opt-out form (N=89 CA, 92 NHW) or were reached by telephone (N=633 CA, 357 NHW). A total of 220 CA and 216 NHW women were eligible and consented to participate. Breast cancer patients were eligible for the study if they met the follow criteria: (1) Chinese or NHW ethnicity, (2) ≥21 years-old at the time of enrollment, (3) stage 0–III primary breast cancer diagnosis, (4) completed primary cancer treatment (surgery, radiation, chemotherapy) 1–5 years prior to recruitment, and (5) no breast cancer recurrence or other cancers. NHW cases were age matched to CA cases (± 5 years). For the present project, women were additionally excluded if they did not complete the food frequency questionnaire (FFQ) (16.3% of participants). The final sample size included 365 breast cancer survivors (N=192 CA, 173 NHW). This study was approved by the Institutional Review Boards at Georgetown University Medical Center, the California Health and Human Services Agency, and the Cancer Prevention Institution of California. Written informed consent were obtained from all study participants.
Data collection
Data were obtained through a one-hour long survey administered via telephone. An optional FFQ and photographs of food serving sizes were mailed to participants to fill at home or report via telephone. Trained, bilingual interviewers interviewed participants in their preferred language. All NHW cases were interviewed in English and about 70% of CA were interviewed in Mandarin or Cantonese.
Treatment-related symptoms
The primary study outcome, treatment-related symptoms, were ascertained by a questionnaire adapted from two existing instruments, the Memorial Symptom Assessment Scale (MSAS) [28] and the Breast Cancer Prevention Trial Symptom Checklist [29]. The MSAS has previously been used in Chinese survivors [30]. Women were asked if they experienced any of 34 possible treatment-related symptoms and its severity within the past 12 months from the interview date. Symptoms were assessed using a 5-level scale, from “not at all” to “very much”. Participants who responded “not at all” to a symptom were categorized as not having the symptom and all other responses were categorized as experiencing the symptom.
The primary outcomes in the present analysis were menopausal symptoms, joint problems, fatigue, hair thinning/loss and memory problems. Menopausal symptoms and joint problems variables were derived by combining several questions. Presence of menopausal symptoms was defined as having any of the following three symptoms: hot flashes or night/cold sweats, vaginal dryness or pain with intercourse, and vaginal discharge. Joint problems encompassed four symptoms: muscle pain, joint stiffness, joint pain, and bone thinning. Individual items of each particular symptom category were summed (ranged from 0–3 for menopausal symptoms and 0–4 for joint problems) and categorized as binary presence/absence of symptoms. Additionally, fatigue, hair thinning/loss, and memory loss were evaluated because they were commonly mentioned symptoms and were previously reported to be influenced by diet (40, 41).
Dietary assessment
A 28-item FFQ, adapted from existing and validated FFQs to ascertain specific food groups of interest among CA and NHW breast cancer survivors, was administered [31–36]. The FFQ ascertained typical intake of cruciferous vegetables (12 questions), allium vegetables (5 questions), soy foods (4 questions), meat/fish (3 questions), green tea (1 question), and alcoholic beverages (2 questions). Participants were asked to indicate how often, on average, they ate each food item over the past three months. For each item there were nine frequency options (never/less than one time a month - 2 or more times a day) and three serving size choices (small, medium, and large). Photographs and descriptions were provided to assist serving size estimation. Isoflavone and glucosinolate intakes were estimated using typical amounts of the bioactive food components reported for each food item. Isoflavone intake was estimated using nutrient databases published by the U.S. Department of Agriculture [37]. Glucosinolate intake was derived from estimates of glucosinolates content in common food sources [38].
Covariates
Patient-reported demographic information included age, race, birthplace, education, health insurance coverage, marital and employment status, and annual household income. Survivors were asked whether they had received any ET, including tamoxifen or aromatase inhibitors (AIs) to prevent breast cancer recurrence. Clinical variables were provided by the cancer registries and included: cancer stage, diagnosis date, age at diagnosis, status of hormonal receptors, and type of primary treatment. Time since diagnosis was estimated using a survivor’s interview date subtracted from the date of diagnosis.
Patient-reported menopausal status at the time of interview and cause (e.g. natural, surgical), height and current weight were also assessed. Menopausal status classification was based on the presence/absence of menstrual cycles, age and whether menopause was related to cancer treatment. Patient-reported menopausal status was classified into 4 groups: postmenopausal, peri-menopausal, treatment-induced menopause and premenopausal. Survivors were classified as postmenopausal if they reported no menstrual cycle for 12 consecutive months or had menopause and were ≥58 years of age. Women who reported lack of regular menstruation, but not for 12 consecutive months, and were <58 years of age were classified as peri-menopausal. Survivors whose menopause was induced by breast cancer treatment or who just completed the treatment and were not sure if periods would return, were classified as treatment-induced menopause. The remaining women were classified as premenopausal.
Physical activity was assessed using the International Physical Activity Assessment Questionnaire (IPAQ) [39,40]. Participants self-reported number of days per week and duration of moderate and vigorous physical activity, and walking. Physical activity was classified into 3 levels: inactive, minimally active, and health enhancing physical activity (HEPA). Metabolic equivalent of task (MET)-minutes per week were calculated following the IPAQ scoring method [41]. HEPA was defined as vigorous activities at least 3 days/week, accumulating at least 1500 MET-minutes/week or any intensity level of activity every day of the week achieving a minimum of 3000 MET-minutes/week. Survivors reporting different intensity activity of at least 600 MET-minutes/week were classified as “minimally active”. Respondents reporting <600 MET-minutes/week were classified as “inactive”.
Statistical Analysis
Descriptive statistics were computed to examine variable distributions. Correlations were evaluated using Pearson correlation. Age-adjusted logistic regression was used to assess associations between population characteristics, breast cancer-related variables (e.g. ET, time since diagnosis and cancer stage), intake of soy and cruciferous vegetable intake and reported symptoms. Cruciferous vegetable (<33.0, ≥ 33.0 to <70.8, ≥70.8 g/day), soy product (no intake, >0 to <24.0, ≥24.0 g/day) glucosinolate intake (≤20.4, >20.4 to <50.1, ≥50.1 mg/day) and isoflavone intake (no intake, >0 to <6.30, ≥6.30 mg/day) were categorized into tertiles.
Multivariable-adjusted logistic regression models were conducted to examine associations between dietary intake and treatment-related symptoms. Results were similar for the whole foods and associated bioactive food components; therefore, whole food results are presented in the primary results. Bioactive food component results are provided in supplementary materials. Models were adjusted for race/ethnicity, age (continuous), BMI (continuous), ET (none, AIs, tamoxifen), menopausal status (pre-, post-, peri-menopause, induced menopause), physical activity (HEPA active, minimally active, or inactive), time since diagnosis (<24, 24-36, >36 months), and cancer stage (0, I, II, III). Covariates were considered if previous research indicated that a variable may be associated with diet or treatment-related symptoms. While radiation and chemotherapy treatment was associated with treatment-related symptoms, it was not associated with dietary intakes nor did it change observed associations, so was not included in final study models. Alcohol intake was also not associated with symptoms in this study population, and therefore, not included in final models.
As consumption of both cruciferous vegetables and soy foods was higher in CA than NHW survivors, we replicated analyses stratified by race/ethnicity. Previous studies suggest possible interactions between ET usage and diet, so analyses were also conducted stratified by ET usage (non-user, tamoxifen user, AI user) [16,42]. Due to limited numbers within ET usage strata, ET findings are presented only in supplementary materials. Tests for interactions between food groups and ethnicity or ET usage were conducted by including a cross product term in multivariable-adjusted models. All analyses were conducted by SAS 9.30 version with significance level defined as a p-value <0.05 or a 95% confidence interval that includes the null value of 1.0.
Results
A majority of women in this study were postmenopausal (47.6%) or perimenopausal (22.4%) (Table 1). The mean age was 57.1 years (SD=10.4). Most survivors were diagnosed with stage 0 (30.1%) or stage I (45.4%) breast cancer and 29.6% were < 2 years post-diagnosis, 30.4% were 24 to <36 months and 40.0% ≥36 months. Hormone receptor positive subtypes were most common (estrogen receptor positive: 62.2%; progesterone receptor positive: 53.7%). HER2 negative tumors were identified in 45.8% of participants, however, 42.2% had unknown HER2 status. Approximately, one quarter of the survivors received chemotherapy and 45.8% received radiation therapy. Endocrine therapy was utilized in 59.2% (34.5% tamoxifen, 24.9% AIs) of survivors. Cruciferous vegetable and soy food intakes ranged from no intake to 864 and 431 g/day, respectively. Mean intakes for cruciferous vegetables and soy foods were 17.1 g/day and 0 g/day in the lowest tertile, and 153.0 g/day and 98.5 g/day in the highest tertile, respectively. Among CA survivors, 44.8% were in the highest tertile for cruciferous vegetable intake and 49.5% for soy food intake, while 22.0% and 20.2% of NHW survivors were in the highest tertiles for each of the respective food types. Cruciferous vegetable intake and soy intake were modestly correlated with each other (r=0.35, p<0.001).
Table 1.
Population characteristics
| Total Population | Non-Hispanic White | Chinese American | |
|---|---|---|---|
|
| |||
| Total N (%) | 365 (100) | 173 (47.4) | 192 (52.6) |
| Age in years (mean, SD) | 57.1 (10.4) | 57.2 (10.5) | 56.9 (10.4) |
| Menopausal status (N, %) | |||
| Premenopause | 47 (13.0) | 21 (12.3) | 26 (13.7) |
| Induced Menopause | 61 (16.9) | 30 (17.5) | 31 (16.3) |
| Perimenopause | 81 (22.4) | 35 (20.5) | 46 (24.2) |
| Postmenopause | 172 (47.6) | 85 (49.7) | 87 (45.8) |
| BMI (kg/m2) (mean, SD) | 24.0 (4.4) | 25.2 (5.1) | 22.9 (3.1) |
| Physical activity (N, %)a | |||
| Active | 110 (30.1) | 77 (44.5) | 33 (17.2) |
| Inactive | 119 (32.6) | 38 (22.0) | 81 (42.2) |
| Minimally active | 136 (37.3) | 58 (33.5) | 78 (40.6) |
| Cancer stage (N, %) | |||
| Stage 0 | 110 (30.1) | 64 (37.0) | 46 (24.0) |
| Stage I | 166 (45.4) | 77 (44.5) | 89 (46.4) |
| Stage II | 47 (12.9) | 22 (12.7) | 25 (13.0) |
| Stage III | 42 (11.5) | 10 (5.8) | 32 (16.7) |
| Endocrine therapy (N, %) | |||
| None | 148 (40.8) | 74 (42.8) | 74 (38.5) |
| Tamoxifen | 126 (34.5) | 60 (34.7) | 66 (34.4) |
| Aromatase inhibitor | 91 (24.9) | 39 (22.5) | 52 (27.1) |
| Lumpectomy (N, %) | |||
| No | 141 (38.6) | 59 (34.1) | 82 (42.5) |
| Yes | 224 (61.4) | 114 (65.9) | 110 (57.3) |
| Mastectomy (N, %) | |||
| No | 228 (62.5) | 114 (65.9) | 114 (59.4) |
| Yes | 137 (37.5) | 59 (34.1) | 78(40.6) |
| Chemotherapy (N, %) | |||
| No | 257 (76.3) | 127 (80.4) | 130 (72.6) |
| Yes | 80 (23.7) | 31 (19.6) | 49 (27.4) |
| Radiation therapy (N, %) | |||
| No | 198 (54.2) | 88 (50.9) | 110 (57.3) |
| Yes | 167 (45.8) | 85 (49.1) | 82 (42.7) |
| Time since diagnosis (N, %) | |||
| <24 months | 108 (29.6) | 48 (27.7) | 60 (31.3) |
| 24–36 months | 111 (30.4) | 49 (28.3) | 62 (32.3) |
| >36 months | 146 (40.0) | 76 (43.9) | 70 (36.5) |
| Estrogen receptor (N, %) | |||
| Positive | 227 (62.2) | 109 (63.0) | 118 (61.5) |
| Negative | 49 (13.4) | 19 (11.0) | 30 (15.6) |
| Unknown | 89 (24.4) | 45 (26.0) | 44 (22.9) |
| Progesterone receptor (N, %) | |||
| Positive | 196 (53.7) | 91 (52.6) | 105 (54.7) |
| Negative | 80 (21.9) | 37 (21.4) | 43 (22.4) |
| Unknown | 89 (24.4) | 45 (26.0) | 44 (22.9) |
| HER2 (N, %) | |||
| Positive | 44 (12.1) | 18 (10.4) | 26 (13.5) |
| Negative | 167 (45.8) | 74 (42.8) | 93 (48.4) |
| Unknown | 154 (42.2) | 81 (46.8) | 73 (28.0) |
| Soy products (N, %)b | |||
| No intake | 104 (28.5) | 73 (42.2) | 31 (16.1) |
| >0 – <24.0 g/day | 131 (35.9) | 65 (37.6) | 66 (34.4) |
| ≥24.0 g/day | 130 (35.6) | 35 (20.2) | 95 (49.5) |
| Isoflavones (N, %)b | |||
| No intake | 104 (28.5) | 73 (42.2) | 31 (16.1) |
| >0 – <6.3 mg/day | 129 (35.3) | 62 (35.8) | 67 (34.9) |
| ≥6.3 mg/day | 132 (36.2) | 38 (22.0) | 94 (49.0) |
| Cruciferous vegetable (N, %)b | |||
| <33.0 g/day | 121 (33.2) | 77 (44.5) | 44 (22.9) |
| ≥33.0 – <70.8 g/day | 120 (32.9) | 58 (33.5) | 62 (32.3) |
| ≥70.8 g/day | 124 (33.9) | 38 (22.0) | 86 (44.8) |
| Glucosinolates (N, %)b | |||
| ≤20.4 mg/day | 121 (33.2) | 70 (40.5) | 51 (26.6) |
| >20.4 – <50.1 mg/day | 120 (32.9) | 55 (31.8) | 65 (33.9) |
| ≥50.1 mg/day | 124 (33.9) | 48 (27.7) | 76 (39.6) |
Active: vigorous physical activity ≥ 3 days/week + ≥1500 MET-minutes/week or ≥3,000 MET-minutes/week engaged in any intensity levels of physical activity; Minimally active: < Active cut-points and ≥600 MET-minutes/week; Inactive: <600 MET-minutes/week.
Tertiles.
Age-adjusted associations between population characteristics, cancer-related variables, cruciferous vegetable and soy intake and treatment-related symptoms are reported on Table 2. NHW women were more likely to report experiencing menopausal symptoms, while CA were more likely to report fatigue, joint problems, hair loss/thinning and memory loss. Compared to postmenopausal women, premenopausal (OR=0.26, 95% CI: 0.09, 0.73) women were less likely to report menopausal symptoms while women with treatment-induced menopause were more likely to report both menopausal symptoms (OR=3.99, 95% CI: 1.40, 11.4) and hair thinning/loss (OR=2.28, 95% CI: 1.01, 5.13). Longer duration post-diagnosis was inversely associated with menopausal symptoms and fatigue. Chemotherapy was associated with all treatment related symptoms, while radiation therapy was associated with menopausal symptoms. Tamoxifen usage (compared to non-ET users) was significantly associated with menopausal symptoms (OR=3.95, 95% CI: 2.28, 6.82). AI usage was statistically significantly associated with reporting menopausal symptoms, fatigue and joint problems relative to non-ET users.
Table 2.
Age-adjusted associations between selected population characteristics and treatment-related symptoms among breast cancer survivors
| Menopausal symptomsb | Fatigue | Joint problemsc | Hair loss or thinning | Memory loss | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
|
| ||||||||||
| N Yes/No | Age-adjusted OR (95% CI)d | N Yes/No | Age-adjusted OR (95% CI)d | N Yes/No | Age-adjusted OR (95% CI)d | N Yes/No | Age-adjusted OR (95% CI)d | N Yes/N o | Age-adjusted OR (95% CI)d | |
|
| ||||||||||
| Race/ethnicity | ||||||||||
| Chinese American | 95/97 | Reference | 116/76 | Reference | 110/82 | Reference | 86/105 | Reference | 77/115 | Reference |
| Non-Hispanic White | 108/65 | 1.77 (1.14, 2.75) | 80/93 | 0.54 (0.35, 0.82) | 76/97 | 0.57 (0.37, 0.86) | 59/114 | 0.61 (0.39, 0.94) | 37/136 | 0.38 (0.24, 0.60) |
| Menopause status | ||||||||||
| Postmenopause | 74/98 | Reference | 76/98 | Reference | 82/90 | Reference | 53/119 | Reference | 47/125 | Reference |
| Perimenopause | 48/33 | 0.86 (0.44, 1.68) | 48/33 | 1.13 (0.59, 2.18) | 39/42 | 0.79 (0.41, 1.51) | 35/46 | 1.40 (0.72, 2.73) | 30/51 | 1.51 (0.75, 3.02) |
| Induced menopause | 55/6 | 3.99 (1.40, 11.4) | 55/6 | 1.78 (0.78, 4.07) | 37/24 | 1.18 (0.53, 2.62) | 35/26 | 2.28 (1.01 5.13) | 21/40 | 1.32 (0.56, 3.10) |
| Premenopause | 23/24 | 0.26 (0.09, 0.73) | 23/24 | 0.68 (0.25, 1.81) | 25/22 | 0.76 (0.29, 2.01) | 21/25 | 1.28 (0.47, 3.49) | 14/33 | 1.05 (0.36, 3.03) |
| Chemotherapy | ||||||||||
| No | 126/131 | Reference | 116/141 | Reference | 118/139 | Reference | 86/171 | Reference | 69/188 | Reference |
| Yes | 102/65 | 2.18 (1.22, 3.90) | 63/17 | 3.80 (2.08, 6.94) | 55/25 | 2.44 (1.41, 4.21) | 47/33 | 2.48 (1.46, 4.21) | 41/39 | 2.88 (1.68, 4.93) |
| Radiation therapy | ||||||||||
| No | 101/97 | Reference | 105/93 | Reference | 100/98 | Reference | 82/116 | Reference | 60/138 | Reference |
| Yes | 102/65 | 2.20 (1.37, 3.54) | 91/76 | 1.34 (0.86, 2.10) | 86/81 | 1.05 (0.68, 1.63) | 63/103 | 1.01 (0.64, 1.58) | 54/113 | 1.14 (0.72, 1.81) |
| Endocrine therapy | ||||||||||
| None | 59/89 | Reference | 67/81 | Reference | 68/80 | Reference | 55/93 | Reference | 43/105 | Reference |
| Tamoxifen | 9630 | 3.95 (2.28, 6.82) | 77/49 | 1.51 (0.91, 2.50) | 62/64 | 0.84 (0.57, 1.12) | 53/72 | 1.06 (0.64, 1.77) | 40/86 | 1.06 (0.62, 1.80) |
| Aromatase Inhibitor | 48/42 | 2.46 (1.39, 4.36) | 52/39 | 2.17 (1.24, 3.80) | 56/35 | 2.32 (1.33, 4.06) | 37/54 | 1.50 (0.85, 2.63) | 31/60 | 1.40 (0.78, 2.51) |
| Time since diagnosis | ||||||||||
| <24 months | 71/37 | Reference | 75/33 | Reference | 63/45 | Reference | 46/62 | Reference | 40/68 | Reference |
| 24–36 months | 52/59 | 0.44 (0.25, 0.79) | 50/61 | 0.35 (0.20, 0.63) | 52/59 | 0.65 (0.38, 1.12) | 48/62 | 1.11 (0.64, 1.92) | 33/78 | 0.75 (0.43, 1.32) |
| >36 months | 80/66 | 0.52 (0.30, 0.90) | 71/75 | 0.36 (0.21, 0.62) | 71/75 | 0.64 (0.38, 1.07) | 51/95 | 0.71 (0.42, 1.20) | 41/105 | 0.66 (0.38, 1.13) |
| Cancer stage | ||||||||||
| Stage 0 | 48/62 | Reference | 47/63 | Reference | 45/65 | Reference | 29/80 | Reference | 18/92 | Reference |
| Stage 1 | 97/69 | 2.26 (1.34, 3.80) | 90/76 | 1.80 (1.09, 2.98) | 86/80 | 1.66 (1.01, 2.72) | 63/103 | 1.73 (1.01, 2.97) | 52/114 | 2.43 (1.31, 4.50) |
| Stage II | 29/18 | 2.03 (0.97, 4.24) | 30/17 | 2.31 (1.12, 4.76) | 27/20 | 1.90 (0.94, 3.84) | 28/19 | 3.72 (1.79, 7.75) | 21/26 | 4.06 (1.86, 8.86) |
| Stage III | 29/13 | 2.25 (1.03, 4.94) | 29/13 | 2.55 (1.18, 5.53) | 28/14 | 2.74 (1.28, 5.84) | 25/17 | 3.37 (1.57, 7.21) | 23/19 | 6.30 (2.81, 14.1) |
| Soy productsa | ||||||||||
| No intake | 66/38 | Reference | 59/45 | Reference | 54/50 | Reference | 41/63 | Reference | 33/71 | Reference |
| >0 – <24.0 g/day | 74/57 | 0.56 (0.32, 0.99) | 72/59 | 0.79 (0.46, 1.36) | 68/63 | 0.94 (0.56, 1.59) | 58/73 | 1.12 (0.65, 1.92) | 43/88 | 1.03 (0.58, 1.80) |
| ≥24.0 g/day | 63/67 | 0.41 (0.23, 0.72) | 65/65 | 0.66 (0.38, 1.12) | 64/66 | 0.84 (0.50, 1.42) | 46/83 | 0.78 (0.45, 1.35) | 38/92 | 0.89 (0.51, 1.58) |
| Cruciferous vegetablesa | ||||||||||
| <33.0 g/day | 72/49 | Reference | 60/61 | Reference | 59/62 | Reference | 45/76 | Reference | 30/91 | Reference |
| ≥33.0 – <70.8 g/day | 73/47 | 1.08 (0.63, 1.85) | 65/55 | 1.22 (0.73, 2.05) | 61/59 | 1.09 (0.66, 1.82) | 56/64 | 1.51 (0.89, 2.55) | 42/78 | 1.58 (0.90, 2.77) |
| ≥70.8 g/day | 58/66 | 0.54 (0.32, 0.93) | 71/53 | 1.36 (0.81, 2.27) | 66/58 | 1.20 (0.72, 1.99) | 44/79 | 0.89 (0.52, 1.52) | 42/82 | 1.51 (0.86, 2.63) |
Tertiles.
Menopausal symptoms: Hot flashes or night/cold sweats, vaginal dryness/pain with intercourse, vaginal discharge.
Joint problems: muscle pain, joint stiffness, joint pain, bone thinning.
Age-adjusted logistic regression.
Soy intake tended to be inversely associated with treatment-related symptoms when compared to no intake, but in multivariable-adjusted models, only fatigue was statistically significantly in the overall population (≥ 24.0 versus 0 g/day, OR=0.43, 95% CI: 0.22, 0.84) (Table 3). In models stratified by race/ethnicity, associations with menopausal symptoms and fatigue only statistically significant in NHW survivors, however, tests for interaction were not statistically significant. Results for isoflavones were similar to associations observed soy foods and treatment-related symptoms (Supplementary Table 1).
Table 3.
Multivariable-adjusted associations between soy intake and treatment-related symptoms among Chinese and non-Hispanic White breast cancer survivors
| Menopausal symptomsb | Fatigue | Joint problemsc | Hair loss or thinning | Memory loss | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
|
| ||||||||||
| N Yes/No | Age-adjusted OR (95% CI)d | N Yes/No | Age-adjusted OR (95% CI)d | N Yes/No | Age-adjusted OR (95% CI)d | N Yes/No | Age-adjusted OR (95% CI)d | N Yes/N o | Age-adjusted OR (95% CI)d | |
|
| ||||||||||
| Soy Productsa | ||||||||||
| Overal | ||||||||||
| No intake | 66/38 | Reference | 59/45 | Reference | 54/50 | Reference | 41/63 | Reference | 33/71 | Reference |
| >0 – <24.0 g/day | 74/57 | 0.47 (0.23, 0.93) | 72/59 | 0.62 (0.33, 1.16) | 68/63 | 0.79 (0.43, 1.44) | 58/73 | 0.89 (0.48, 1.65) | 43/88 | 0.82 (0.43, 1.58) |
| ≥24.0 g/day | 63/67 | 0.51 (0.25, 1.03) | 65/65 | 0.43 (0.22, 0.84) | 64/66 | 0.56 (0.29, 1.06) | 46/83 | 0.66 (0.34, 1.26) | 38/92 | 0.53 (0.26, 1.06) |
| P-trend | 0.08 | 0.01 | 0.08 | 0.21 | 0.07 | |||||
| Non-Hispanic White | ||||||||||
| No intake | 51/22 | Reference | 39/34 | Reference | 35/38 | Reference | 23/50 | Reference | 15/58 | Reference |
| >0 – <24.0 g/day | 39/26 | 0.36 (0.13, 1.01) | 29/36 | 0.47 (0.20, 1.09) | 27/38 | 0.49 (0.21, 1.15) | 24/41 | 0.87 (0.35, 2.13) | 16/49 | 1.17 (0.47, 2.90) |
| ≥24.0 g/day | 18/17 | 0.29 (0.09, 0.96) | 12/23 | 0.25 (0.09, 0.72) | 14/21 | 0.49 (0.18, 1.31) | 12/23 | 0.89 (0.32, 2.45) | 6/29 | 0.68 (0.21, 2.14) |
| P-trend | 0.03 | 0.008 | 0.11 | 0.80 | 0.62 | |||||
| Chinese | ||||||||||
| No intake | 15/16 | Reference | 20/11 | Reference | 19/12 | Reference | 18/13 | Reference | 18/13 | Reference |
| >0 – <24.0 g/day | 35/31 | 0.52 (0.17, 1.61) | 43/23 | 0.94 (0.31, 2.77) | 41/25 | 1.27 (0.46, 3.50) | 34/32 | 0.60 (0.22, 1.65) | 27/39 | 0.56 (0.20, 1.61) |
| ≥24.0 g/day | 45/50 | 0.61 (0.21, 1.76) | 53/42 | 0.68 (0.24, 1.90) | 50/45 | 0.71 (0.27, 1.85) | 34/60 | 0.44 (0.16, 1.16) | 32/63 | 0.38 (0.14, 1.05) |
| P-trend | 0.54 | 0.38 | 0.26 | 0.10 | 0.06 | |||||
| P-interactione | 0.71 | 0.31 | 0.60 | 0.55 | 0.35 | |||||
Tertiles.
Menopausal symptoms: Hot flashes or night/cold sweats, vaginal dryness/pain with intercourse, vaginal discharge.
Joint problems: muscle pain, joint stiffness, joint pain, bone thinning.
Multivariable logistic regression adjusted for age (continuous), ethnicity (Chinese American, non-Hispanic White), menopausal status (premenopause, treatment induced menopause, perimenopause, postmenopause), BMI (continuous), physical activity (active, minimally active, inactive), endocrine therapy (none, tamoxifen, aromatase inhibitor), time since diagnosis (<24 months, 24-36 months, >36 months), and cancer stage (0, I, II, III).
Test for interaction between soy intake and ethnicity. Logistic regression models additionally including cross-product interaction term for soy intake and ethnicity.
Cruciferous vegetable intake was inversely associated with menopausal symptoms in the overall population (≥ 70.8 versus <33.0 g/day, adjusted OR=0.50, 95% CI: 0.25, 0.97). (Table 4). When stratified by race/ethnicity, cruciferous vegetable intake remained inversely, but not statistically significantly, associated with menopausal symptoms. Cruciferous vegetable intake was not associated with other treatment-related symptoms in multivariable-adjusted models overall. Higher intake was significantly inversely associated with hair loss/thinning among CA, but not NHW survivors (P-interaction=0.08). Additionally, higher intake was positively associated (P-trend=0.03) with memory loss among NHW survivors, but inversely, though not statistically significantly (P-trend=0.31), associated with memory loss among CA survivors (P-interaction=0.02). However, few NHW survivors reported memory loss, so this result should be interpreted with caution. Associations between glucosinolate intake and symptoms were consistent with observed associations with cruciferous vegetable intake (Supplementary Table 2).
Table 4.
Multivariable-adjusted association between cruciferous vegetable intake and treatment-related symptoms among Chinese and non-Hispanic White breast cancer survivors
| Menopausal symptomsb | Fatigue | Joint problemsc | Hair loss or thinning | Memory loss | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
|
| ||||||||||
| N Yes/No | Age-adjusted OR (95% CI)d | N Yes/No | Age-adjusted OR (95% CI)d | N Yes/No | Age-adjusted OR (95% CI)d | N Yes/No | Age-adjusted OR (95% CI)d | N Yes/N o | Age-adjusted OR (95% CI)d | |
|
| ||||||||||
| Cruciferous vegetablesa | ||||||||||
| Overall | ||||||||||
| <33.0 g/day | 72/49 | Reference | 60/61 | Reference | 59/62 | Reference | 45/76 | Reference | 30/91 | Reference |
| ≥33.0 – <70.8 g/day | 73/47 | 0.90 (0.46, 1.74) | 65/55 | 0.97 (0.53, 1.75) | 61/59 | 0.88 (0.50, 1.57) | 56/64 | 1.41 (0.78, 2.54) | 42/78 | 1.32 (0.70, 2.48) |
| ≥70.8 g/day | 58/66 | 0.50 (0.25, 0.97) | 71/53 | 1.26 (0.68, 2.32) | 66/58 | 1.08 (0.59, 1.95) | 44/79 | 0.68 (0.37. 1.28) | 42/82 | 1.24 (0.56, 2.39) |
| P-trend | 0.04 | 0.46 | 0.80 | 0.26 | 0.51 | |||||
| Non-Hispanic White | ||||||||||
| <33.0 g/day | 50/27 | Reference | 34/43 | Reference | 30/47 | Reference | 21/56 | Reference | 10/67 | Reference |
| ≥33.0 – <70.8 g/day | 37/21 | 1.44 (0.53, 3.92) | 29/29 | 1.22 (0.53, 2.78) | 28/30 | 1.20 (0.52, 2.75) | 23/35 | 2.47 (1.00 6.11) | 15/43 | 2.40 (0.92, 6.30) |
| ≥70.8 g/day | 21/17 | 0.72 (0.23, 2.22) | 17/21 | 0.99 (0.39, 2.51) | 18/20 | 1.20 (0.47, 3.03) | 15/23 | 1.55 (0.57, 4.19) | 12/26 | 2.00 (1.03, 8.74) |
| P-trend | 0.71 | 0.93 | 0.65 | 0.25 | 0.03 | |||||
| Chinese | ||||||||||
| <33.0 g/day | 22/22 | Reference | 26/18 | Reference | 29/15 | Reference | 24/20 | Reference | 20/24 | Reference |
| ≥33.0 – <70.8 g/day | 36/26 | 0.96 (0.35, 2.62) | 36/26 | 0.82 (0.31, 2.13) | 33/29 | 0.76 (0.31, 1.85) | 33/29 | 0.83 (0.33, 2.04) | 27/35 | 0.71 (0.28, 1.81) |
| ≥70.8 g/day | 37/49 | 0.42 (0.16, 1.09) | 54/32 | 1.27 (0.51, 3.14) | 48/38 | 1.00 (0.42, 2.37) | 29/56 | 0.31 (0.13, 0.75) | 30/56 | 0.61 (0.25, 1.51) |
| P-trend | 0.05 | 0.53 | 0.89 | 0.006 | 0.31 | |||||
| P-interactione | 0.86 | 0.76 | 0.63 | 0.08 | 0.02 | |||||
Tertiles.
Menopausal symptoms: Hot flashes or night/cold sweats, vaginal dryness/pain with intercourse, vaginal discharge.
Joint problems: muscle pain, joint stiffness, joint pain, bone thinning.
Multivariable logistic regression adjusted for age (continuous), ethnicity (Chinese American, non-Hispanic White), menopausal status (premenopause, treatment induced menopause, perimenopause, postmenopause), BMI (continuous), physical activity (active, minimally active, inactive), endocrine therapy (none, tamoxifen, aromatase inhibitor), time since diagnosis (<24 months, 24-36 months, >36 months), and cancer stage (0, I, II, III).
Test for interaction between cruciferous vegetable intake and ethnicity. Logistic regression model additionally including cross-product interaction term for cruciferous vegetable intake and ethnicity.
In models stratified by ET usage, soy food intake was statistically significantly inversely associated fatigue among non-ET users and joint problems in AI users. Among tamoxifen users, soy food intake was not associated with symptoms. Cruciferous vegetable intake was statistically significantly inversely associated with menopausal symptoms among AI users (≥70.8 versus <33.0 g/day, OR=0.13, 95% CI: 0.02, 0.62), whereas this inverse association was not statistically significant among non-users and tamoxifen users (P-interaction=0.20) (Supplementary Table 3). Tests for interaction were not statistically significant but numbers of participants in strata were small, so these results should be interpreted with caution.
Discussion
Presently, little is known of the effects of foods on menopausal symptoms or other treatment-related symptoms in breast cancer survivors [43,44]. In the combined population of CA and NHW breast cancer survivors, higher cruciferous vegetable was associated with lower odds of reporting experiencing menopausal symptoms and higher soy food intake was inversely associated with fatigue and menopausal symptoms. However, when stratified by race/ethnicity, soy intake associations with fatigue and menopausal symptoms were only statistically significant among NHW survivors. Associations between glucosinolates, isoflavones and treatment-related symptoms were consistent with observed associations for the corresponding food sources.
While the safety of soy intake has been questioned for breast cancer patients [45], several studies have reported lower risk of breast cancer recurrence [46–49] and mortality [50,51] among women with higher soy intakes. In our study, the intake of soy foods was linked to reduced prevalence of menopausal symptoms among breast cancer survivors. The exact biological mechanisms behind the menopausal symptoms are not well-understood, but may be due to the decrease in estrogen levels, and possibly, the corresponding impact on other hormones, such as gonadotropins [52]. Soy isoflavones are weakly estrogenic compounds, which may reduce menopausal symptoms by activating estrogen receptors in a low estrogen environment, though the exact mechanism remains unclear [11,12]. Previous research suggests soy isoflavones may modestly reduce menopausal symptoms in healthy peri- and postmenopausal women [55]. However, among breast cancer survivors isoflavone supplementation for 4 to 12 weeks did not alleviate menopausal symptoms, which could be related to the duration, amount or type of soy supplementation product [18,20,56]. Conversely, an observational study among Chinese survivors found that higher soy isoflavone intake increased hot flashes at 36 months post-breast cancer diagnosis [16]. Possible explanations for the differences between our results and the previous observational study include: 1) the prior study involved Chinese women living in China and our study involved Chinese and NHW women living in the USA; 2) the former study assessed fewer menopausal symptoms, whereas our study measured multiple; and 3) patients in the prior study had a much higher soy intake than in our study sample. We additionally observed stronger associations among NHW (lower soy intake) compared to CA women (higher soy intake). It is possible that the benefits of soy intake are more evident in women with lower intakes relative to no intake, or that prevalence of women either reporting experiencing menopausal symptoms, no soy intake, or both were too low among the CA survivors to detect an association [54]. Of note, the prevalence of menopausal symptoms is reported to be lower in menopausal Asian women, which has been attributed to the higher soy content in their diet [54,53]. Alternatively, there may be differences in soy metabolism by race/ethnicity resulting in differential exposure to bioactive components in soy [57].
There was a suggestive inverse association between soy intake and fatigue. Research on soy and fatigue is limited, but a double-blind randomized placebo controlled trial of equol, a metabolite of another soy isoflavone (daidzein), observed statistically significant decreases in reported fatigue, among other psychosocial indicators, in Japanese women [58]. In our study, higher soy intake was inversely, albeit not statistically significantly, associated with joint problems, hair loss/thinning and memory loss. Isoflavones can increase secretion of insulin-like growth factor-1, which in turn promotes hair growth [59]. In animal studies, isoflavones have shown to preserve memory function [60,61], while a human study previous reported improvement in cognitive function with isoflavone intake [62].
In our study, cruciferous vegetable consumption was inversely associated with menopausal symptoms. While research on cruciferous vegetables and treatment-related symptoms is lacking, suggestive inverse associations between fruit and vegetable intake and night sweats and hot flashes were previously reported in a population of middle-aged Australian women [63]. One possible mechanism by which cruciferous vegetable intake might influence menopausal symptoms is via changes in regulation of estrogen metabolism enzymes, including cytochrome P450 1A1 (CYP1A1) [23,25–27]. Human trial data observed changes in estrogen metabolite profiles following supplementation of indole-3-carbinol, a metabolite of glucosinolates present in cruciferous vegetables [23]. We also observed a suggestive inverse association between higher cruciferous vegetable intake and hair loss/thinning among CA women. Long term ET-associated hair loss/thinning in breast cancer survivors is not well-studied and possible mechanisms by which cruciferous vegetable intake may limit them remain to be elucidated. One possible mechanism may be mediation of inflammation by compounds present in cruciferous vegetable [22,24], however, since this association was only present in CA survivors, this also may be chance association.
A strength of the present study was inclusion of both NHW and CA breast cancer survivors which provided a wide range of soy and cruciferous vegetable intake. A considerable additional strength is that this study provides important data on an understudied population: Asian American breast cancer survivors. Another strength was the data collection by phone, which allowed interviewers to follow-up on survey questions and were conducted in both English and Chinese. There are also several limitations, including the cross-sectional study design, which can result in temporality bias and limits causal inference. Dietary data were ascertained via FFQ, which has important limitations, including potential exposure misclassification. Although the FFQ ascertained detailed intake of selected vegetables and soy products, it was not a comprehensive FFQ. Therefore, we could not compute energy and individual nutrient intake and may have residual confounding from dietary factors not collected, including other types of fruits and vegetables. However, our analysis did control for two major determinants of energy intake, BMI and physical activity. Small sample size may have impacted our ability to detect associations, particularly for evaluating whether associations differ by race/ethnicity and endocrine-therapy usage. Finally, biospecimens were not collected in this population, so we were unable to measure estrogen and dietary-related biomarkers, which would have strengthened the study findings and provided possible mechanistic insights.
In conclusion, intake of soy and cruciferous vegetables may by associated with menopausal symptoms and fatigue in breast cancer survivors. Research on the role of diet and treatment-related effects in breast cancer survivors remains understudied, particularly in diverse study populations. To confirm study findings, additional research is needed that explores the possible relationship between diet and breast cancer treatment-related symptoms incorporating measurement of biomarkers and prospective data collection in a larger, diverse study population.
Supplementary Material
Supplementary Table 1-Soy isoflavone intake and treatment-related symptoms among Chinese and non-Hispanic White breast cancer survivors
Supplementary Table 2-Glucosinoate intake and treatment-related symptoms among Chinese and non-Hispanic White breast cancer survivors
Supplementary Table 3-Cruciferous vegetable and soy intake, endocrine therapy and treatment-related symptoms among Chinese and non-Hispanic White breast cancer survivors
Acknowledgments
Funding
This research was supported by a Lance Armstrong Foundation Young Investigator Award and a National Cancer Institute R21 Grant# CA139408.
This research was supported by a Lance Armstrong Foundation Young Investigator Award and a National Cancer Institute R21 Grant# CA139408. The collection of cancer incidence data used in this study was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885; the National Cancer Institute’s Surveillance, Epidemiology and End Results Program under contract HHSN261201000140C awarded to the Cancer Prevention Institute of California, contract HHSN261201000035C awarded to the University of Southern California, and contract HHSN261201000034C awarded to the Public Health Institute; and the Centers for Disease Control and Prevention’s National Program of Cancer Registries, under agreement # U58DP003862-01 awarded to the California Department of Public Health. The ideas and opinions expressed herein are those of the author(s). Endorsement by the State of California Department of Public Health, the National Cancer Institute, and the Centers for Disease Control and Prevention or their Contractors and Subcontractors is not intended nor should be inferred.
Footnotes
Conflict of Interest Statement
The authors declare that they have no conflicts of interest.
Disclaimers: The project described was supported by Award Number R21CA139408 from the National Cancer Institute and Lance Armstrong Foundation Young Investigator Award. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies including National Cancer Institute or the National Institutes of Health.
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Associated Data
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Supplementary Materials
Supplementary Table 1-Soy isoflavone intake and treatment-related symptoms among Chinese and non-Hispanic White breast cancer survivors
Supplementary Table 2-Glucosinoate intake and treatment-related symptoms among Chinese and non-Hispanic White breast cancer survivors
Supplementary Table 3-Cruciferous vegetable and soy intake, endocrine therapy and treatment-related symptoms among Chinese and non-Hispanic White breast cancer survivors