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Keywords:

  • breast cancer;
  • recurrences;
  • metabolic syndrome

Abstract

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Several studies have shown that hormonal, metabolic and inflammatory mechanisms may affect breast cancer progression. We tested the prognostic value of metabolic syndrome in 110 postmenopausal breast cancer patients, who participated in a 1-year dietary intervention study. The risk of adverse events after 5.5 years of follow-up was examined by Cox' proportional hazard modelling, adjusting for hormone receptor status, stage at diagnosis and serum testosterone level, which were shown to significantly affect prognosis. The adjusted hazard ratio of recurrence for the presence of metabolic syndrome at baseline was 3.0 (95% CI 1.2–7.1). Combining metabolic syndrome and serum testosterone, the adjusted hazard ratio of recurrence among women with metabolic syndrome and testosterone levels higher than 0.40 ng/ml (median value) was 6.7 (95% CI 2.3–19.8) compared with that among women without metabolic syndrome and testosterone levels ≤0.40 ng/ml. The results suggest that metabolic syndrome may be an important prognostic factor for breast cancer. © 2006 Wiley-Liss, Inc.

The prevalence of metabolic syndrome is increasing in parallel with increasing breast cancer incidence worldwide.1, 2 Several studies have suggested that low HDL-cholesterol,3 high blood glucose,4 high triglycerides5 and other aspects of the metabolic syndrome, such as postmenopausal overweight,1 abdominal obesity,6, 7 hypertension,8 high levels of insulin and insulin-like growth factor I (IGF-I),7, 9, 10, 11 are associated with breast cancer risk. Metabolic and hormonal parameters related to metabolic syndrome have been suggested to affect breast cancer prognosis too.12, 13, 14, 15

This is the first report addressing the issue whether breast cancer prognosis is affected by metabolic syndrome, defined by 3 or more of the following indicators: fasting glycaemia ≥110 mg/dl, HDL-cholesterol <50 mg/dl, triglycerides ≥150 mg/dl, waist circumference ≥88 cm, systolic pressure ≥130 mmHg and diastolic pressure ≥85 mmHg.16

If confirmed, these results showing a significantly worse prognosis of patients with metabolic syndrome could have important implications for lifestyle intervention to prevent or decelerate cancer progression.

Patients and methods

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

One hundred and ten postmenopausal women (mean age: 56.8 ± 5.6 years) operated for breast cancer since at least a year (4.6 ± 4.4 years on average), not undergoing chemotherapy, and with no clinical evidence of disease recurrence, volunteered to participate in a dietary intervention study in which they were requested to follow kitchen courses and modify their diet for 1 year with the aim of reducing insulin and sex hormone levels (The Diana-2 Study).12 All patients signed an informed consent and the study was approved by the Institutional Review Board and the Ethical Committee of the Milan National Cancer Institute. Results on hormonal changes and the prognostic values of baseline hormone levels (testosterone, oestradiol and insulin) have been published elsewhere.12, 17

The prognostic effect of metabolic syndrome more than 5.5 years after recruitment is now evaluated.

The statistical analysis focused on the risk of breast cancer recurrence (local relapse, distant metastasis and contralateral breast cancer) in relation to the baseline presence of metabolic syndrome. The means of baseline hormone levels in patients with metabolic syndrome were compared with those of patients without metabolic syndrome. The effect of metabolic syndrome on the risk of recurrence was assessed by hazard ratios and 95% confidence intervals (CI), with the Cox proportional hazards model. The following covariates were considered as potential confounders: age (in tertiles), extent of disease at diagnosis [as size of the primary (T1, T2 or more) and axillary node status (N−, N+)] oestrogen and progesterone receptor status (positive, negative), current tamoxifen treatment (yes or no) and time between diagnosis and recruitment (1–2 years, 3–5 years, more than 5 years). T, N and hormone receptor status proved to be significant confounders and were retained in the analytical model. Since our previous results12 showed that serum testosterone levels were strongly and significantly associated with recurrence, adjustment for testosterone (in tertiles) was performed in the present analysis. The proportional hazards assumption was checked for each model by scaled Shoenfeld residuals analysis. The analysis was carried out using the STATA 8.0. statistical package.

Results

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

At the beginning of the study, 16 patients were affected by metabolic syndrome. Patients with metabolic syndrome showed significantly higher levels of testosterone (0.49 ± 0.15 (SD) versus 0.41 ± 0.15 ng/ml, p value of difference: 0.04), oestradiol (8.67 ± 6.54 versus 5.82 ± 3.69 pg/ml, p value of difference:0.01), insulin (12.4 ± 6.58 versus 7.4 ± 3.00 μUI/ml, p value of difference:<0.01) and significantly lower levels of sex hormone-binding globulin (SHBG) (46.3 ± 28.13 versus 67.8 ± 29.75 nmol/l, p value of difference: <0.01), conditions known to be associated to higher breast cancer risk.11, 18 The average values of the factors defining metabolic syndrome in patients with and without metabolic syndrome were as follows: waist circumference 90.6 versus 81.8 cm, fasting glycaemia 103 versus 90.8 mg/dl, triglycerides 155.6 versus 99.7 mg/dl, HDL-cholesterol 49.8 versus 56.7 mg/dl, systolic pressure 137.7 versus 129.8 mmHg and diastolic pressure 85.3 versus 81.2 mmHg. Table I shows the general characteristics of 110 women who participated in the study and the distribution of factors used to define metabolic syndrome.

Table I. Characteristics of 110 Breast Cancer Patients Who Participated in The Intervention Trial
VariablesNumber of patients
  • 1

    Values in parentheses indicate percentage.

  • 2

    Available for 87 patients.

Age
 44–5548 (44)1
 56–6034 (31)
 61–6928 (25)
Time between diagnosis and recruitment
 1–2 years36 (33)
 3–5 years38 (34)
 6+ years36 (33)
BMI at baseline
 20–2444 (42)
 25–2938 (37)
 30+22 (21)
 T >2 cm35 (32)
 Node (N) positive40 (37)
 Oestrogen receptor positive62 (56)
 Waist circumference ≥88 cm36 (33)
 Fasting glycaemia ≥110 mg/dl7 (6)
 Triglycerides ≥150 mg/dl15 (14)
 HDL-cholesterol <50 mg/dl31 (28)
 Systolic pressure2 ≥130 mmHg46 (53)
 Diastolic pressure2 ≥85 mmHg29 (33)

On testing the relationship between hormonal treatment at the time of examination and all factors defining metabolic syndrome, it was found that only HDL-cholesterol was significantly and positively associated with tamoxifen use. No significant association was found between the same factors and tumour size, axillary node status or hormone receptor status, i.e. the main pathological parameters considered for prescribing adjuvant treatment.

Overall, 32 patients developed recurrences, either local,4 distant16 or contra-lateral breast cancer.12 Eight of them (1 local, 4 distant, 3 contra-lateral) had metabolic syndrome at baseline.

The crude hazard ratio of recurrence for the presence of metabolic syndrome at baseline was 2.4 (95% confidence interval (CI) 1.1–5.3). The hazard ratio of recurrence, adjusted for pathological prognostic factors and serum testosterone, was 3.0 (95% CI 1.2–7.1). We have then combined testosterone and metabolic syndrome as hormonal and metabolic factors that significantly affected the prognosis (Table II). The adjusted hazard ratio of recurrence among women with metabolic syndrome and testosterone levels higher than 0.40 ng/ml (the median value) was 6.7 (95% CI 2.3–19.8) compared with that among women without metabolic syndrome and with testosterone levels up to 0.40 ng/ml. Women belonging to the other categories (those with testosterone levels above the median value but without metabolic syndrome analysed together with the few women with metabolic syndrome but low testosterone levels) showed an adjusted hazard ratio of 3.4 (95% CI 1.4–8.3). The adjusted hazard ratio of recurrences for each factor used to define metabolic syndrome showed a positive association (nonstatistically significant) only with glycaemia, systolic and diastolic pressure.

Table II. Distribution of 110 Breast Cancer Patients With or Without Recurrences According to Metabolic Syndrome and Serum Testosterone Levels at Baseline1
Metabolic syndromeTestosteroneng/mlRecurrencesHazard ratio (age adjusted)Hazard ratio (fully adjusted)2
YesNo
  • 1

    Age- and fully adjusted hazard ratio are reported for each category.

  • 2

    Adjusted for age and pathological prognostic factors.

  • 3

    Values in parentheses indicate 95% CI.

No≤0.4074611
Yes≤0.40131.7 (0.2–14.3)32.2 (0.2–19.4)3
No>0.4017243.3 (1.4–8.2)3.8 (1.5–9.5)
Yes>0.40755.9 (2.0–17.0)6.7 (2.3–19.8)

After 1 year dietary intervention, the metabolic syndrome persisted only in 3 patients (1 in whom the condition recurred and 2 in whom it did not). Testosterone levels decreased both in patients who subsequently had recurrences and in those who did not. The former, however, still presented very high levels (0.51 ± 0.15 ng/ml versus 0.37 ± 0.11 ng/ml).

Discussion

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

In the present study on the risk of breast cancer recurrence during 5.5 years of follow-up, the presence of a metabolic syndrome at baseline emerged as an important prognostic factor for breast cancer recurrences, especially if associated with high serum levels of testosterone. This relationship was not confounded by Tamoxifene treatment at the time of examination. None of the factors defining metabolic syndrome was significantly associated with prognosis, when considered alone.

Our previous studies have shown that levels of sex hormones, and anthropometric and metabolic variables related to metabolic syndrome can be favourably modified by a comprehensive change in diet, in which the consumption of refined carbohydrates and saturated fats is reduced and the consumption of whole-grain cereals, pulses and vegetables is increased17, 19, 20 It has also suggested that these changes may favourably influence the prognosis of breast cancer.12

If the predictive value of metabolic syndrome is confirmed on larger series of patients, its evaluation shall become part of the standard diagnostic workup of breast cancer patients, and dietary or other medical intervention to prevent or control the syndrome should be considered. The present results however suggest that, to be effective, the correction of metabolic syndrome must be sufficient to obtain a substantial decrease in serum testosterone.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

The DIANA-2 study was financed by the Europe Against Cancer Programme of the European Union, the Italian Association for Cancer Research (AIRC) and the CARIPLO Foundation.

References

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
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