Profiles of lipids, blood pressure and weight changes among premenopausal Chinese breast cancer patients after adjuvant chemotherapy

Background Adjuvant chemotherapy improves outcome of patients with early breast cancer. However, chemotherapy may be associated with long term toxicities. In this retrospective cohort study, the objectives were to determine body weight, body mass index (BMI), blood pressure and fasting lipids levels of young premenopausal Chinese breast cancer patients after adjuvant chemotherapy. Potential factors associated with these parameters were identified. Methods Eligibility criteria include premenopausal Chinese patients who were diagnosed to have stage I-III breast cancer within 3–10 years, age < 45 and having received adjuvant chemotherapy at the time of breast cancer diagnosis. Information at initial breast cancer diagnosis were retrieved from patients’ medical records and include age at diagnosis, tumor characteristics, anti-cancer treatments, blood pressure and body weight and height. At study entry, all patients had additional background demographics collected, as well as blood pressure, body weight and fasting serum lipid profiles measured. Incidence of chemotherapy-related amenorrhoea (CRA) and menopause were determined. Factors associated with weight gain, hypertension and dyslipidaemias were analyzed. Results Two hundred and eighty patients were studied. The median age at breast cancer diagnosis was 41 years (range: 24–45). The median time from breast cancer diagnosis to study entry was 5.0 years. The median age at study entry was 46.5 years (range: 28–54). 91.1% developed CRA; 48.9% had become menopausal and 10% were peri-menopausal. Between initial breast cancer diagnosis and the time of study entry, the median weight gain was 1.8 kg; 63.2% gained weight by >2%; 52.1% were overweight/obese; 30.7% had hypertension. Abnormal total-cholesterol and LDL-cholesterol occurred in 34.3% and 56.1% respectively. On multivariate analyses, older age was associated with reduced risk while occurrence of CRA and having received taxane-containing regimens were associated with increased risk of weight gain. Oestrogen-receptor positivity was associated with reduced risk while overweight/obese statuses were associated with increased risk of hypertension. Use of tamoxifen was associated with reduced risk of abnormal LDL-cholesterol. Weight gain, overweight/obese, older age, progression to post/peri-menopausal status at study entry, having received corticosteroid premedication before adjuvant chemotherapy and having received taxane-containing adjuvant chemotherapy were associated with increased risk of dyslipidaemias. Conclusion Among young premenopausal Chinese breast cancer patients who had received adjuvant chemotherapy, the current study has revealed that although there was only a median weight gain of 1.8 kg, there was a nearly 60% increase in abnormal BMI. Further, a significant proportion of patients were detected to have hypertension and dyslipidaemias. Interventional studies with lifestyle modifications are warranted. Electronic supplementary material The online version of this article (doi:10.1186/s12905-017-0409-8) contains supplementary material, which is available to authorized users.


Background
In China, breast cancer is the most common female malignancy, with an age standardized rate of 27.96 per 100,000 population [1]; the corresponding figure is relatively higher in Hong Kong at 64.6 per 100,000 population, with over 80% of newly diagnosed breast cancer patients having diagnosed with early stage disease [2]. For women with early stage breast cancer who have undergone curative surgery, adjuvant therapies have shown to improve disease-free and overall survival. Anticancer treatment, especially cytotoxic chemotherapy, is associated with immediate as well as long-term toxicities, which may affect the quality of life and well-being of cancer survivors [3,4]. Some of the chemotherapy-related long term toxicities include chemotherapy-related amenorrhoea (CRA) and early menopause, as well as anthropometric and metabolic changes that could lead to increased cardiovascular risk [5,6].
Weight gain is a common occurrence in women diagnosed with breast cancer [7][8][9][10]. Patients who underwent adjuvant chemotherapy had reportedly gained more weight than those treated with hormonal or radio-therapies [9][10][11][12]; such difference continued to be observed over years, and a return to initial weight following weight gain was infrequent [9]. With old chemotherapeutic regimens, studies in the UK and the US had indicated that women who underwent chemotherapy gained an average of 2.5-6.7 kg in weight, although gains in excess of 10 kg had not been uncommon [13,14]. Using contemporary chemotherapy regimens that included taxanes as well as anthracyclines, a French study reported a mean weight gain of 3.9 kg 1 year after treatment [15]. Apart from weight gain and obesity which is associated with detrimental effect on health profiles, anti-cancer drugs, specifically the anthracyclines and anti-human epidermal growth factor receptor 2 (HER2) agents that are commonly used in breast cancer, could cause cardiotoxicity and may further increase the cardiovascular risk of the patients concerned [16]. While change in menopausal status and increased body weight have been well-linked to the use of adjuvant chemotherapy, the association of these changes with cardiovascular comorbidities, specifically, aspects on blood pressure and lipids profiles, are less well-known.
The objectives of this retrospective cohort study on young premenopausal Chinese women with early breast cancer in Hong Kong were to (1) determine the body weight, body mass index (BMI), blood pressure and fasting lipids levels of young premenopausal breast cancer patients after adjuvant chemotherapy; and (2) identify potential factors associated with these parameters.

Methods
Between September 2008 and February 2011, eligible breast cancer patients who were attending the breast cancer follow-up clinic of the Prince of Wales Hospital were approached for study enrolment. Eligibility criteria included female of Chinese ethnicity, a history of stage I-III breast cancer within 3-10 years, premenopausal, age younger than 45 years and having received adjuvant chemotherapy at the time of breast cancer diagnosis. Patients were excluded if they had evidence of disease recurrence. Patients who received ovarian ablation as part of the endocrine therapy or had hysterectomy prior to breast cancer diagnosis were also excluded. Eligible patients identified during their follow up visits were consented for the study. The study was approved by the Joint CUHK-NTEC Clinical Research Ethics Committee of the Chinese University of Hong Kong and Hong Kong Hospital Authority.

Data collection
Clinical details at the time of breast cancer diagnosis were retrieved from individual patient's medical records. These included patient's age at breast cancer diagnosis, cancer characteristics (stage, oetrogen receptors [ER], progesterone receptors [PR] and HER2 status of the breast tumour) and information on treatment she received for her breast cancer (type of breast surgery, details of adjuvant radiotherapy, chemotherapy, tamoxifen and trastuzumab, and history of corticosteroid premedication during chemotherapy). Individual patient's blood pressure, body height and weight, measured by clinic staff at the time of diagnosis, were also retrieved from the medical records.
At study entry, patients' demographics (education level, employment history, level of family income, smoking and alcohol history, family history of breast cancer and number of live births before breast cancer diagnosis) were collected. Each patient had blood pressure and body weight measured by a research assistant. Each patient was asked to complete a study questionnaire in which they recalled their menstruation history with the assistance of a research assistant within the same hospital visit. In the questionnaire, patients were asked in details on the following: [1] last menstrual period (LMP) before commencement of chemotherapy; [2] after commencement of chemotherapy, presence or absence of a period of amenorrhoea with dates; [3] in case of occurrence of amenorrhoea, whether there was subsequent return of menstruation with dates; [4] for patients who had resumption of menstruation, any subsequent amenorrhoea with dates. For patients who did not experience amenorrhoea during chemotherapy, the subsequent menstrual history was further collected similarly. LMP prior to study entry was determined for each patient. Fasting blood was taken for lipid profiles, which included total-cholesterol, low density lipoprotein (LDL-) cholesterol, high density lipoprotein (HDL-) cholesterol and triglyceride levels.

Definitions
CRA was defined as amenorrhoea for ≥3 months during and within 12 months after the completion of adjuvant chemotherapy [17]. Menopause was defined in line with World Health organization (WHO) criteria as 12 months of amenorrhoea with last menstrual period (LMP) ≥12 months after chemotherapy and before study entry [18].
At study entry, weight gain was defined as an increase in body weight of >2% when compared to the weight at breast cancer diagnosis [13], prior to the start of adjuvant therapies. According to the WHO criteria for Asians, BMI categories of underweight, normal weight, overweight and obesity were defined as <18.5, 18.5-< 23, 23-< 25, and >/= 25.0 kg/m2 respectively [19].

Statistical analysis
Statistical analysis was performed by SAS version 9.3. Continuous variables were expressed as means with standard deviation or median with range as appropriate. Baseline continuous variables were compared by Student's t-test or Mann Whitney U test as appropriate, and categorical variables were compared by Chi-square test. All statistical tests were two-sided, and p values <0.05 were regarded as significant.
Univariate logistic regression was performed to identify any potential factors associated with weight gain, hypertension and dyslipidaemias post-chemotherapy.
Stepwise multivariate logistic regression analysis that included significant factors was conducted.

Results
In total, 300 breast cancer patients were approached for study entry, 14 of them declined participation. As a result, 286 patients were consented to participate in this study. Two patients failed to meet inclusion criteria as they received neo-adjuvant therapy for their stage IIIb breast cancers, four patients withdrew with the reason that they didn't have time to perform the blood tests after consent. As a result, 280 eligible patients entered the study. Table 1 shows the patients' background demographics, tumour characteristics, and anti-cancer treatments received after breast cancer diagnosis. With regards to educational level, majority (67%) of the patients received secondary school education, 17% had primary school education and 16% had tertiary or higher level of education. On employment, 45% were on full time employment, 16% had part-time employment and the remaining 38% were either unemployed or had retired. With respect to family income, 9.6% of patients had monthly family income less than HK$5000, 54% had income of HK$5000-25,000, 30% had income of HK$25000-50,000 and 7% had income over HK$50,000.
Two hundred and fifty-five (91.1%) had experienced CRA. At study entry, 137 patients were postmenopausal and 28 were peri-menopausal. The median age of menopause was 44 years (range: 34-52). Details of the menstrual history of all patients were described in a previous report [14].

Body weight and BMI at breast cancer diagnosis and at study entry
The median weight of patients at breast cancer diagnosis was 54.6 kg (range: 39.0-89.0), this increased by 1.8 kg to 56.4 kg (range: 39.5-92.6) at study entry. At study entry, 177 patients (63.2%) had gained weight by >2%, including 121 who gained >/=5%.

Lipid profiles at study entry
Two hundred and seventy-one patients had serum fasting lipids determined. Ninety-three patients (34.3%) had high total-cholesterol, 152 (56.1%) had high LDL- Analysis for risk factors associated with weight gain, hypertension and dyslipidaemias after adjuvant chemotherapy were independent factors for weight gain. Table 3 shows the outcomes of univariate and multivariate analyses on factors associated with hypertension. Univariate analysis revealed that estrogen receptor positivity    084-4.517, p = 0.0292) at study entry were associated with higher likelihood of hypertriglyceridaemia. Factors that were analyzed but were not found to associate with any component of dyslipidaemias on multivariate analysis include: education level; employment and family income statuses; history of smoking and excessive alcohol intake; having child birth before breast cancer diagnosis; family history of first degree relative with breast cancer; breast ER/PR and HER2  Table  S1 lists the outcomes of univariate analyses on potential factors in association with abnormal total cholesterol, LDL-cholesterol, HDL-cholesterol ad triglyceride levels.

Discussion
Until recently, clinical follow-up of cancer survivors have mainly focused on survival and early detection of cancer recurrence. The advancement in the use of adjuvant therapies has improved outcomes of breast cancer patients, and as a result longer survivals are expected. With increased survival, it is anticipated that long-term toxicities associated with cancer treatments may become more evident; these include effects on physical morbidities and psychosocial symptoms. To our knowledge, the present study is one of the first to assess cardiovascular risk profiles of young premenopausal Chinese patients who had received modern-day adjuvant chemotherapy; apart from body weight and BMI alterations, changes on blood pressure and fasting lipids measurements have also been assessed. As the incidence of breast cancer among young Asian females has been noted to be rapidly increasing, information on these aspects among the studied population is of particular interest [22]. Although the cause of weight gaining after breast cancer diagnosis is unclear, it has been suggested that there may be ethnic differences. In the WHEL study [9], Asian-Americans were found to have a lower risk of gaining weight after chemotherapy than other races. To date, only a few studies have addressed the issue on weight changes in Asian patients. In a study from Shanghai China, breast cancer patients who received adjuvant chemotherapy had mean weight gains of 1.0, 2.0 and 1.0 kg at 6, 18 and 36 months after diagnosis. However, details of the type and duration of chemotherapy were not described [10]. A Korean study involved 195 pre-and post-menopausal patients who received adjuvant chemotherapy (mainly anthracyclines and taxanes regimens) with/without endocrine therapy [23]. Although 10% of the studied population gained weight by >5% at 1 year, the mean weight change was in fact, at a loss of 0.34 kg, indicating that the majority of Korean breast cancer patients did not gain weight after adjuvant treatment. In a third study [24], 98 pre-and postmenopausal Chinese breast cancer patients underwent weight assessment prior to and immediately after having received doxorubicin and/or taxane-containing adjuvant chemotherapy; the results revealed that they had an overall mean weight loss of 0.4 kg. The present study assessed only young premenopausal Chinese patients with a protracted interval of 5 years after adjuvant chemotherapy, 63% had gained weight by >2% and the average gain was 1.8 kg; although this figure appeared to be small, one cannot overlook the proportion of patients who were detected to have abnormal BMI, as this had increased by nearly 60%, from 33% at breast cancer diagnosis to 52% at study entry. The figure is worrisome; according to the World Health Organization (WHO) criteria, significant health risks is associated with obesity, which has been defined as a body mass index (BMI) of 25.0 and over for Asian population [19].
A number of factors have been suggested to lead to weight gain and obesity after adjuvant chemotherapy. These include hyperphagia, younger age, menopausal status, reduced physical activity, longer duration of adjuvant chemotherapy, use of corticosteroids premedication during chemotherapy and pre-treatment body weight [7,8,11,[24][25][26][27][28]. The present study has confirmed that weight gain is more common among premenopausal patients who were younger at diagnosis and who experienced CRA; in addition, those who had prior taxanecontaining regimen were also at higher risk. The latter could be associated with the use of corticosteroids during chemotherapy, as had been suggested by the study reported by Goodwin et al. [11] Dexamethasone is given as standard premedication prior to taxane therapy to avoid hypersensitivity reactions, and is also part of the optimal antiemetic regimen offered for patients on anthracyclinecontaining chemotherapy.
Only a few studies have addressed dyslipidaemias after adjuvant chemotherapy in breast cancer patients. In a recent report on Italian pre-and post-menopausal patients with early breast cancer, increase in cholesterol was found in patients who received chemotherapy only, but not in those who also received endocrine therapy [6]. The occurrence of abnormal total-and LDL-cholesterol among premenopausal patients has been attributed to chemotherapy-induced ovarian dysfunction [29][30][31]. The observation from a recent study lends support to this by showing that peri-menopausal patients undergoing taxane-based adjuvant chemotherapy had the largest change in lipids profiles when compared to pre-or postmenopausal patients, implicating that transition in hormone status may play a role [32]. Tamoxifen has been well-reported to lower total-and LDL-cholesterol [33][34][35][36] as early as 3 months after treatment initiation [34,35]. Further, the administration of adjuvant tamoxifen after chemotherapy has been observed to reverse dyslipidaemias in premenopausal patients [30]. In the present study, a significant proportion of patients were found to have dyslipidaemias after chemotherapy. While tamoxifen was associated with reduced risk of abnormal LDL-cholesterol, increased likelihood of dyslipidaemias was associated with older age, post/peri-menopausal status after chemotherapy, weight gain or overweight/obese, and having received taxane-containing chemotherapy or corticosteroids premedication during adjuvant chemotherapy.
The present study has a few limitations; there is a lack of data on energy expenditures (e.g., physical activity levels, basal metabolic rates), caloric intakes and body composition. Further, blood pressure measurement was only performed once during clinic visit; none-the-less, this provides a glimpse on the cardiovascular status of the studied population. Dyslipidaemia may contribute to adverse cardiovascular outcomes. In this study, over 30% of the patients were detected to be hypertensive. Multivariate analysis on risk of hypertension showed that estrogen receptor positivity was associated with decreased likelihood while overweight/obese was associated with increased likelihood of raised blood pressure. It has to be noted that additional 2 factors were identified on univariate analysis-use of tamoxifen reduced (OR 0.557, 95% CI 0.313-0.990, p = 0.0462) while high LDLcholesterol (OR 1.762, 95% CI 1.027-3.021, p = 0.0396) increased the likelihood of hypertension (Additional file 1: Table S1); these factors may have intertwining effects.
It has to be noted that long term toxicities of chemotherapy are not confined to menstrual disturbances, weight and BMI changes. The occurrence of hypertension and dyslipidaemias based on findings from the current study needs to be confirmed with further studies. Studies on bone health have reported that women with premature ovarian failure after adjuvant chemotherapy have increased risk for bone loss when compared to their counterparts who remain premenopausal [37,38]. Although cognitive dysfunction among patients who developed menopause after chemotherapy has not been confirmed in earlier studies [39,40], further assessment with improved methodology is required. Moreover, it has been shown that over 30% of cancer survivors suffer from fatigue and sleep disturbances, anxiety, depression and impairment of physical functioning affecting their quality of life [41,42].

Conclusions
In summary, the present study suggests that younger premenopausal patients and those who experienced CRA were more susceptible to weight gain and abnormal BMI, which in turn were associated with adverse effects on cardiovascular profiles with dyslipidemias and hypertension. Several reports have suggested that weight gain and obesity affect breast cancer outcomes [43,44], and a recent report has implicated that high LDL-cholesterol at diagnosis [45] may also have prognostic importance. At the same time, weight gain and obesity not only affect the physical wellbeing of a patient, but have been associated with impaired quality of life among breast cancer patients after adjuvant therapy [46]. These provide good justifications for encouraging lifestyle changes to patients after breast cancer diagnosis [6,23,47]. In many developing countries, educational level and economical status are the major determinants of reaching healthcare facilities and preventive interventions. The lack of weight gain in Korean patients after chemotherapy has been attributed in part to patient education, which encouraged patients to maintain healthy body weight [23]. As such, data on interventional studies with lifestyle modifications to control weight and dyslipidaemia are valuable and may provide information to health care providers to better manage patients for impacts of long-term sequelae of anti-cancer treatments.

Additional file
Additional file 1: Table S1.