Breast cancer (BC) is a disease characterized by the growth of malignant cells in the mammary glands. BC is the most frequent cancer in women, which is malignant in most cases, and is the leading cause of cancer related deaths among women worldwide. It accounts for about 28% of all cancers in Europe and United States.[1] In Jordan, BC is the most frequent cancer type amongst female cancers, accounting for about 37% of all cancers and about 19% of all newly diagnosed cancer cases followed by colorectal cancer. According to a published study in the United Kingdom, around 7% of female BC is related to modifiable lifestyle and environmental factors.[2] Although, many risk and prognostic factors of BC have been documented, an insight view of BC severity and prognosis is still not clarified.[3] Evidences suggest that cardio-metabolic risk factors such as dyslipidemia and hypertension (HTN) may have different influences on BC severity and pathogenesis.[4, 5, 6] Dyslipidemia is characterized by an elevation in total cholesterol concentration, low-density lipoprotein cholesterol (LDL-C), triglyceride (TG) concentrations and a reduction in high-density lipoprotein cholesterol (HDL-C). Mechanisms for such relationship between dyslipidemia and BC risk are unknown; however, previous studies proposed that abnormal lipid metabolism along with insulin resistance may be related to BC pathogenesis and BC subtypes.[4] Moreover, BC tissues had faster TG turnover in comparison to normal tissue.[6] Evidence of possible effect of dyslipidemia and HTN on BC risk is inconclusive and very limited.[4,5,7]
In Jordan, dyslipidemia and HTN are significantly prevalent among Jordanian females and males.[8, 9, 10] However, there are no studies on BC severity and HTN, nor on dyslipidemia risk factors. Furthermore, studies that evaluate the impact of treatment exposure on dyslipidemia and HTN are also lacking. Subsequently, the objective of the current study is to evaluate the interactive role of BC on Dyslipidemia and HTN risk among Jordanian women according to the type of treatment exposure and menopausal status.
In this study, 396 Jordanian female patients diagnosed with breast cancer (BC) aged between 25–65 years attending BC clinics at the Jordanian Royal Medical Services in Jordan for the management and follow-up of their conditions during the period from January 2013 to July 2014. Patients were screened for leptin hormone level. The experimental design was prospective observational that permitted to include 134 newly-diagnosed BC patients who were naïve to any type of treatment interventions and 262 recently-diagnosed BC patients (up to three months) who were exposed to any type of treatment interventions. Recently, group members were sub-divided into sub-groups to control exposure to chemotherapy. The study design also permitted to include pre- and postmenopausal BC patients for hormonal balance control. The sample size (396) was statistically sound and accounts for about 50% of BC cases in the year 2011. The median age of females with BC in Jordan is 51 years old, and 80% of the cases age ranged between the ages of 25 and 65 years old.[11] Exclusion criteria was also determined; any clinical or laboratory evidence of congestive heart failure, coronary disease, chronic renal failure, polycystic ovary syndrome, thyroid diseases, pregnancy and lactation. Moreover, subjects below 25 or above 65 years of age, type I diabetes mellitus, epilepsy and those taking medical herbs were also excluded. Also, any subject who did not fit the inclusion criteria was excluded. This study was conducted according to the Declaration of Helsinki (2008, including 2013 amendments) and willingly; all participants had read and signed an informed consent form at the start of the study. The Royal Medical Services Ethical Committee approved this study (reference number 1/2013).
A validated and reliable questionnaire was adopted for data collection which included personal information, health, anthropometric and biochemical measurements.
Anthropometric indicators comprised of: height, weight, waist circumference (WC) and hip circumference (HC) were measured in duplicates with subjects lightly clothed and without shoes. These indicators were performed by the investigator following the methodological protocol.[12] The body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. The BMI ≥ 30 kg/m2 was considered obese.[13] The waist to hip ratio (WHpR) was calculated as WC divided by HC, while the waist to height ratio (WHtR) was calculated as WC divided by Height.
Blood samples were collected after minimum 12 hours of fasting. The serum had been harvested and stored at −80°C for analysis. Biochemical measurements were analyzed in Princess Eman Center for Laboratory Research and Science. The following laboratory measurements were performed in duplicates for each subject and the mean values were taken in subsequent calculations for biomarkers such as fasting blood glucose (FBG), fasting blood insulin (FBI) and C-peptide. For the analysis of triglycerides (TG), total cholesterol (TC), high density lipoprotein (HDL-C) and low density lipoprotein (LDL-C) in human serum, the enzymatic colorimetric assay was applied. The upper normal limits used for TC and LDL-C, were 200 mg/dl and 150 mg/dl, respectively. Lower limit for HDL was < 50 mg/dl. Plasma glucose was determined by the glucose dehydrogenase method (Wako Pure Chemical Industries, Ltd., Osaka, Japan). C-peptide was measured by a solid-phase, two-site chemiluminescent immunoassay (IMMULITE 2000 C-peptide assay, Siemens AG, Erlangen, Germany). The fasting blood insulin levels were quantitatively determined by chemiluminescent microparticle immunoassay (CMIA) technology (ARCHITECT Insulin assay, Abbott Laboratories, IL, USA). The Manual Enzyme-Linked Immunosorbent Assay (ELISA) was used for the quantitative determination of leptin levels in serum by an enzyme immunoassay method (dbc-Diagnostics Biochem Canada Inc., Canada). The insulin sensitivity was then calculated using HOMA according to the following formula[14]:
Two blood pressure readings were recorded in an upright sitting position by a licensed staff nurse using a standard mercury sphygmomanometer after seating the subjects for at least 15 minutes. The average value was recorded and blood pressure was considered high if SBP ≥ 130 mmHg and/or DBP ≥ 85 mmHg.[15] The cut-off points for SBP, DBP, TG, and HDL-C were determined based on Alberti
Statistical analyses were performed using Statistical Package for the Social Sciences (SPSS), version 10.0 (SPSS Inc., Chicago, USA). For all analyses, a probability value of < 0.05 was considered statistically significant. Results were expressed according to the study needs as either frequency distribution with their percentages (%) or means ± standard error of mean (SEM). Frequency distribution and percentages or means ± SEM were performed for the health characteristics, prevalence of dyslipidemia and hypertension, and the menopausal status was compared according to the type of treatment exposure. The independent sample t-test or the chi-squared test were used between high density lipoprotein (HDL-C) and low density lipoprotein (LDL-C), systolic and diastolic blood pressure, and menopausal status in addition to various BC status.
Dyslipidemia and hypertension characteristics of the study sample according to treatment exposure are shown in Table 4.1. Systolic blood pressure (SBP) was higher (
Dyslipidaemia and hypertension characteristics according to treatment exposure(1, 2, 3)
119.1 | 1.1a | 119.5 | 1.2a | 123.0 | 0.9b | 121.9 | 0.8a | 120.9 | 0.6 | |
78.4 | 1.0a | 78.0 | 0.8a | 79.6 | 0.7a | 79.1 | 0.5a | 78.8 | 0.5 | |
47.8 | 0.8a | 42.9 | 1.0b | 47.6 | 0.7a | 45.6 | 0.6b | 46.4 | 0.5 | |
126.9 | 9.0a | 141.0 | 3.4a | 128.8 | 2.8a | 132.8 | 2.2a | 130.8 | 3.4 | |
195.7 | 5.8a | 221.8 | 8.9b | 205.9 | 5.6b | 211.1 | 4.7b | 205.9 | 3.7 |
1. Values are given as mean ± SEM.
2. Values in rows with different superscripts are significantly different (p < 0.05).
3. Abbreviations and definitions: newly diagnosed: newly-diagnosed: breast cancer patients who are not exposed to any type of interventions; recently-diagnosed: breast cancer patients within 3 months of diagnosis who are either exposed (chemo) or not exposed (non-chemo) to chemical therapy; SEM: stander error of mean; SBP: systolic blood pressure, DBP: diastolic blood pressure, TC: total cholesterol; TG: triglycerides; HDL-C: high density lipoprotein cholesterol; LDL-C: low density lipoprotein cholesterol.
Prevalence of the dyslipidemia risk factors and hypertension according to treatment exposure are presented in Table 4.2. The prevalence of elevated SBP (≥ 130 mmHg) was significantly (
Prevalence of the dyslipidemia risk factors and hypertension according to treatment exposure(1, 2, 3, 4)
14 | 10.4a | 8 | 9.3a | 34 | 19.3b | 42 | 16.0b | 56 | 14.1 | ||
24 | 17.9a | 11 | 12.8a | 38 | 21.6a | 49 | 18.7a | 73 | 18.4 | ||
31 | 23.1 | 10 | 11.6 | 49 | 27.8 | 59 | 22.5 | 90 | 22.7 | ||
82 | 61.2a | 70 | 81.4b | 112 | 63.6a | 182 | 69.5b | 264 | 66.7 | ||
102 | 76.1a | 73 | 84.9b | 143 | 81.2b | 216 | 82.4b | 318 | 80.3 | ||
90 | 67.2a | 75 | 87.2b | 137 | 77.8b | 212 | 80.9b | 302 | 76.3 | ||
7 | 5.2 | 2 | 2.3 | 10 | 5.7 | 12 | 4.6 | 19 | 4.8 |
1. Values given as number of patients (n) and their percentages out of (N).
2. Values in rows with different superscripts are significantly different (p < 0.05).
3. Cut-off points were based on Alberti
4. Abbreviations and definitions: newly-diagnosed: breast cancer patients who are not exposed to any type of interventions; recently-diagnosed: breast cancer patients within 3 months of diagnosis who are either exposed (chemo) or not exposed (non-chemo) to chemical therapy; SEM: stander error of mean; SBP: systolic blood pressure, DBP: diastolic blood pressure, TC: total cholesterol; TG: triglycerides; HDL-C: high density lipoprotein cholesterol; LDL-C: low density lipoprotein cholesterol.
The study patients who are on anti-hypertensive or lipid lowering agents.
Prevalence of dyslipidemia risk factors and hypertension in pre and post-menopause according to treatment exposure are shown in Table 4.3. The prevalence of abnormal TG and HDL-C respectively, was significantly higher (
Prevalence of dyslipidemia risk factors and hypertension in pre and postmenopause according to treatment exposure(1, 2, 3, 4, 5)
6 | 4.5 | 8 | 6.0 | 13 | 5.0 | 29 | 11.1 | 19 | 4.8 | 37 | 9.3 | |
8 | 6.0 | 16 | 11.9 | 20 | 7.6 | 29 | 11.1 | 28 | 7.1 | 45 | 11.4 | |
48 | 35.8 | 34 | 25.4 | 104 | 39.7 | 78 | 29.9 | 152 | 38.4 | 112 | 28.3 | |
56 | 41.8 | 46 | 34.3 | 116 | 44.3 | 100 | 38.3 | 172 | 43.4 | 146 | 36.9 |
1. Documented international cut-off points: Alberti
2. Values are given as number of patients (n) and their percentages out of (N).
3. (*) Significantly (p < 0.05) different between pre and postmenopausal women for each treatment exposure and whole sample.
4. Cross differences between treatment exposure groups were not significant (p > 0.05).
5. Abbreviations and definitions: newly diagnosed: breast cancer patients who are not exposed to any type of interventions; recently diagnosed: breast cancer patients within 3 months of diagnosis who are either exposed (chemo) or not exposed (non-chemo) to chemical therapy; SBP: systolic blood pressure; DBP: diastolic blood pressure; TG: triglycerides; HDL-C: high density lipoprotein.
Dyslipidemia and hypertension characteristic in pre and postmenopausal women according to treatment exposure are shown in Table 4.4. In postmenopausal BC patients, SBP was higher (
Dyslipidemia and hypertension characteristic in pre and postmenopause women according to treatment exposure(1, 2, 3, 4, 5)
117.1 | 1.5 | 121.1 | 1.7a | 118.5 | 0.9 | 136.2 | 1.2b | 118.0 | 0.8 | 129.3 | 1.0 | |
76.6 | 1.4 | 80.9 | 1.1 | 78.3 | 0.6 | 80.2 | 1.0 | 78.0 | 0.6 | 80.0 | 0.7 | |
47.9 | 0.9 | 47.7 | 1.6 | 44.8 | 0.8 | 46.7 | 0.9 | 46.0 | 0.6 | 47.0 | 0.8 | |
182.5 | 6.9 | 215.3 | 9.6 | 201.7 | 6.1 | 223.5 | 7.4 | 195.0 | 4.7 | 221.0 | 5.9 |
1. Documented international cut-off points: Alberti,
2. Values are given as mean ± SEM.
3. (*) Significant differences (p < 0.05) between pre and postmenopausal women for treatment exposure groups and whole sample.
4. Values in rows with different superscripts are significantly different among treatment exposure groups (p < 0.05). None of other values in rows show significant differences (p > 0.05).
5. Abbreviations and definitions: newly diagnosed: breast cancer patients who are not exposed to any type of interventions; recently diagnosed: breast cancer patients within 3 months of diagnosis who are either exposed (chemo) or not exposed (non-chemo) to chemical therapy; SBP: systolic blood pressure; DBP: diastolic blood pressure; TG: triglycerides; HDL: high density lipoprotein; SEM: stander error of mean.
Age-controlled partial correlation coefficients are presented in Table 4.5. The WHtR and WC respectively were significantly (
Age-controlled partial correlation coefficients of dyslipidemia risk factors and hypertension with obesity indices and selected biomarkers in the study sample(1–2)
0.04 | 0.08 | 0.12 | 0.08 | 0.10 | 0.14** | 0.03 | |
0.01 | 0.17*** | 0.15** | 0.13* | 0.08 | 0.10* | −0.02 | |
−0.11* | −0.11* | −0.09 | −0.13** | −0.02 | 0.02 | 0.03 | |
0.05 | 0.16*** | 0.08 | 0.15** | −0.11* | 0.03 | 0.02 |
1. *: (p < 0.05);
: (p < 0.01);
: (p < 0.001).
2. Abbreviations and definitions: newly diagnose: BMI: body mass index; WC: waist circumferences cm; WHtR: waist to height ratio; WHpR: waist to hip ratio; HOMA: homeostasis model assessment according to the following formulas[14]: Log (HOMA) as log [FBG (mmol/L) × FBI (μU/ml)/22.[15]
In this study, the prevalence of known cases of dyslipidemia was 5%. Nevertheless, high triglycerides (TG) and low high density lipoprotein cholesterol (HDL-C) were observed in 80% and 67% of study sample, respectively. Results from this study seem to be higher than those reported in non-BC patients in Jordan. Studies investigating dyslipidemia in breast cancer (BC) patients are scarce. A study by Hammoudeh
In the current study, the prevalence of high TG and low HDL-C level were significantly different among recently-and newly-diagnosed BC patients. These differences may be due to possible medical interventions such as chemotherapy or surgery. Present study showed that prevalence of high TG and low HDL-C level in premenopausal women was higher than in postmenopausal women, but the mean value of TG level was significantly higher (
In the present study, overt hypertension (HTN) was observed in almost 23% of BC patients. In Jordan, studies that investigate the link between HTN and BC in Jordan are absent. In a study by Hammoudeh
In the present study, SBP, in recently-diagnosed BC and in those taking chemotherapy, was found higher than in newly-diagnosed patients. These findings are consistent with a study by Aparicio-Gallego
In this study, the prevalence of both SBP and DBP is higher in postmenopausal than premenopausal women. This result is consistent with a Latin American study, where both SBP and DBP were associated with increased BC risk in postmenopausal women, a matter that suggests the role of increased insulin resistance and obesity.[24] Similar results have been reported by other studies.[25] However, in a study by Agnoli
The available evidence regarding the relationship between HTN and BC risk are inconsistent and variable.[26] In the present study, both SBP and DBP were correlated with HOMA, whereas DBP was strongly correlated to WC and central obesity; there are other studies that showed positive correlation between HTN and insulin resistance.[27] Former Jordanian studies established a high prevalence of insulin resistance and obesity indices among BC women.[28,29] Obesity is a risk factor for both postmenopausal BC and HTN.[24] Studies in which BMI is controlled, the relation between HTN and BC was found to be significant with 20% increased risk of BC in postmenopausal women with HTN.[25] However, a study by Peeters
In conclusion, dyslipidemic and hypertensive biomarkers were prevalent among BC patients. Moreover, the risk increased with obesity and age, as it was higher in postmenopausal BC women. Furthermore, treatments’ exposure especially to chemotherapy increased the risk of dyslipidemia and hypertension. This may be considered as biomarker for BC prognosis after exposure to treatments and warranted a closer attention by health care professionals, in order to improved outcomes after diagnosis and treatment exposure with more concern regarding postmenopausal BC women.
To the best of authors’ knowledge, this study is the first in Jordan to evaluate the concomitance between lipid profile and HTN among BC women. As for limitations, however, the study suffered from limited sample size since it was conducted in only one tertiary hospital. Moreover, there are some structural limitations regarding the study design.