Metabolic Syndrome and Tumour Responses to Chemotherapy
Purpose: Breast cancer is associated with adverse outcomes in patients with the metabolic syndrome phenotype. To study this further, we examined the relationship between serum metabolite levels and the components of metabolic syndrome with treatment outcomes in breast cancer.
Methods: A total of 88 women with measurable breast cancer were studied; their serum metabolites as assessed by H nuclear magnetic resonance spectroscopy, blood pressure, lipids, glucose, body mass index and waist circumference were recorded and correlated with treatment response.
Results: We identified metabolic syndrome in approximately half of our cohort (42 patients) and observed a significant trend (P = 0.03) of increased incidence of metabolic syndrome in partial response (33.3%), stable disease (42.9%) and progressive disease groups (66.1%). High blood sugar predicted a poor response (P < 0.001). Logistic regression of metabonomic data demonstrated that high lactate (P = 0.03) and low alanine (P = 0.01) combined with high glucose (P = 0.01) were associated with disease progression.
Conclusions: Metabolic syndrome is commonly observed in metastatic breast cancer and these patients have poorer outcomes. These data, which support our previous findings, suggest that high blood glucose as part of metabolic syndrome is associated with a poor response in breast cancer. They also validate new therapeutic approaches that focus on metabolism.
Metabolic syndrome, a cluster of disorders including hypertension, type II diabetes, dyslipidemia and obesity, is associated with a high risk for cardiovascular disorders and a variety of other conditions. Of its components, obesity is associated with cancers of oesophagus, colon, breast (postmenopausal), kidney and the endometrium; metabolic and hormonal abnormalities may contribute directly or indirectly to an environment for tumour growth.
It is well known that breast cancer is associated with poorer outcomes in patients with underlying disorders, which include the components of metabolic syndrome. A number of overlapping features link breast cancer with metabolic syndrome, including hyperinsulinaemia, altered sex steroid metabolism, increased oxidative stress and extraglandular estrogen production. A growing body of evidence indicates that breast cancer patients with obesity, insulin resistance and diabetes have a poorer prognosis and that interventions targeted towards these phenotypes can improve cancer outcomes. Recently, it has been shown that diabetic patients with breast cancer receiving metformin during neoadjuvant chemotherapy have higher pathologic complete response (pCR) rates compared with diabetics not receiving metformin, while in the Women's Intervention Nutrition Study, women randomly allocated to a low-fat diet had an increased relapse-free survival. In a further well-publicised study, women who ate more vegetables and exercised had improved survival.
In the adjuvant setting, we have demonstrated that in those who rapidly gained weight several metabolite levels, notably lactate and alanine, were positively associated with and prognostic for weight gain (receiver operator characteristic area under the curve > 0.77; P < 0.05). Serum metabolites were measured using a metabolic profiling approach (metabonomics/metabolomics) based on nuclear magnetic resonance (NMR) spectroscopy. While in vivo magnetic resonance imaging and spectroscopy has been widely used to localise tumours and characterise response, solution state NMR analysis of blood serum and plasma from cancer patients has been primarily focused on defining biomarkers for early detection of malignancy; there are very few studies dealing with prognostication or response to therapy.
Tumour cells exhibit a number of significant metabolic perturbations such as the Warburg effect that are already exploited in diagnosis and therapy and that could provide a rich source of predictive biomarkers. However, in our previous study, the response of serum metabolite levels to treatment was independent of adjuvant/neoadjuvant status; thus, we hypothesised that the metabolic signature associated with weight gain was not the result of tumour metabolism but rather reflected an underlying phenotype with a propensity towards high adiposity, consistent with metabolic syndrome. To investigate this further, we sought for the first time to correlate the triad of metabolic syndrome, metabonomic profiles and treatment response, including their components, aiming to establish and validate the role of these factors in women with breast cancer.
Abstract and Introduction
Abstract
Purpose: Breast cancer is associated with adverse outcomes in patients with the metabolic syndrome phenotype. To study this further, we examined the relationship between serum metabolite levels and the components of metabolic syndrome with treatment outcomes in breast cancer.
Methods: A total of 88 women with measurable breast cancer were studied; their serum metabolites as assessed by H nuclear magnetic resonance spectroscopy, blood pressure, lipids, glucose, body mass index and waist circumference were recorded and correlated with treatment response.
Results: We identified metabolic syndrome in approximately half of our cohort (42 patients) and observed a significant trend (P = 0.03) of increased incidence of metabolic syndrome in partial response (33.3%), stable disease (42.9%) and progressive disease groups (66.1%). High blood sugar predicted a poor response (P < 0.001). Logistic regression of metabonomic data demonstrated that high lactate (P = 0.03) and low alanine (P = 0.01) combined with high glucose (P = 0.01) were associated with disease progression.
Conclusions: Metabolic syndrome is commonly observed in metastatic breast cancer and these patients have poorer outcomes. These data, which support our previous findings, suggest that high blood glucose as part of metabolic syndrome is associated with a poor response in breast cancer. They also validate new therapeutic approaches that focus on metabolism.
Introduction
Metabolic syndrome, a cluster of disorders including hypertension, type II diabetes, dyslipidemia and obesity, is associated with a high risk for cardiovascular disorders and a variety of other conditions. Of its components, obesity is associated with cancers of oesophagus, colon, breast (postmenopausal), kidney and the endometrium; metabolic and hormonal abnormalities may contribute directly or indirectly to an environment for tumour growth.
It is well known that breast cancer is associated with poorer outcomes in patients with underlying disorders, which include the components of metabolic syndrome. A number of overlapping features link breast cancer with metabolic syndrome, including hyperinsulinaemia, altered sex steroid metabolism, increased oxidative stress and extraglandular estrogen production. A growing body of evidence indicates that breast cancer patients with obesity, insulin resistance and diabetes have a poorer prognosis and that interventions targeted towards these phenotypes can improve cancer outcomes. Recently, it has been shown that diabetic patients with breast cancer receiving metformin during neoadjuvant chemotherapy have higher pathologic complete response (pCR) rates compared with diabetics not receiving metformin, while in the Women's Intervention Nutrition Study, women randomly allocated to a low-fat diet had an increased relapse-free survival. In a further well-publicised study, women who ate more vegetables and exercised had improved survival.
In the adjuvant setting, we have demonstrated that in those who rapidly gained weight several metabolite levels, notably lactate and alanine, were positively associated with and prognostic for weight gain (receiver operator characteristic area under the curve > 0.77; P < 0.05). Serum metabolites were measured using a metabolic profiling approach (metabonomics/metabolomics) based on nuclear magnetic resonance (NMR) spectroscopy. While in vivo magnetic resonance imaging and spectroscopy has been widely used to localise tumours and characterise response, solution state NMR analysis of blood serum and plasma from cancer patients has been primarily focused on defining biomarkers for early detection of malignancy; there are very few studies dealing with prognostication or response to therapy.
Tumour cells exhibit a number of significant metabolic perturbations such as the Warburg effect that are already exploited in diagnosis and therapy and that could provide a rich source of predictive biomarkers. However, in our previous study, the response of serum metabolite levels to treatment was independent of adjuvant/neoadjuvant status; thus, we hypothesised that the metabolic signature associated with weight gain was not the result of tumour metabolism but rather reflected an underlying phenotype with a propensity towards high adiposity, consistent with metabolic syndrome. To investigate this further, we sought for the first time to correlate the triad of metabolic syndrome, metabonomic profiles and treatment response, including their components, aiming to establish and validate the role of these factors in women with breast cancer.
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