A Low-Glucose Eating Pattern Improves Biomarkers of Postmenopausal Breast Cancer Risk: An Exploratory Secondary Analysis of a Randomized Feasibility Trial

Postmenopausal breast cancer is the most common obesity-related cancer death among women in the U.S. Insulin resistance, which worsens in the setting of obesity, is associated with higher breast cancer incidence and mortality. Maladaptive eating patterns driving insulin resistance represent a key modifiable risk factor for breast cancer. Emerging evidence suggests that time-restricted feeding paradigms (TRF) improve cancer-related metabolic risk factors; however, more flexible approaches could be more feasible and effective. In this exploratory, secondary analysis, we identified participants following a low-glucose eating pattern (LGEP), defined as consuming energy when glucose levels are at or below average fasting levels, as an alternative to TRF. Results show that following an LGEP regimen for at least 40% of reported eating events improves insulin resistance (HOMA-IR) and other cancer-related serum biomarkers. The magnitude of serum biomarkers changes observed here has previously been shown to favorably modulate benign breast tissue in women with overweight and obesity who are at risk for postmenopausal breast cancer. By comparison, the observed effects of LGEP were similar to results from previously published TRF studies in similar populations. These preliminary findings support further testing of LGEP as an alternative to TRF and a postmenopausal breast cancer prevention strategy. However, results should be interpreted with caution, given the exploratory nature of analyses.

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Insulin resistance and breast cancer incidence and mortality in postmenopausal women in the Women’s Health Initiative

Cancer ◽

10.1002/cncr.33002 ◽

2020 ◽

Vol 126 (16) ◽

pp. 3638-3647

Author(s):

Kathy Pan ◽

Rowan T. Chlebowski ◽

Joanne E. Mortimer ◽

Marc J. Gunther ◽

Thomas Rohan ◽

...

Keyword(s):

Breast Cancer ◽

Insulin Resistance ◽

Women's Health ◽

Postmenopausal Women ◽

Cancer Incidence ◽

Breast Cancer Incidence ◽

Women's Health Initiative ◽

Health Initiative ◽

Incidence And Mortality ◽

The Women’S Health Initiative

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Associations of Insulin Resistance and Adiponectin With Mortality in Women With Breast Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.26.4473 ◽

2011 ◽

Vol 29 (1) ◽

pp. 32-39 ◽

Cited By ~ 163

Author(s):

Catherine Duggan ◽

Melinda L. Irwin ◽

Liren Xiao ◽

Katherine D. Henderson ◽

Ashley Wilder Smith ◽

...

Keyword(s):

Breast Cancer ◽

Insulin Resistance ◽

Cancer Mortality ◽

Cancer Survival ◽

Breast Cancer Mortality ◽

Breast Cancer Survival ◽

Overweight And Obesity ◽

Model Assessment ◽

All Cause Mortality ◽

Low Levels

Purpose Overweight or obese breast cancer patients have a worse prognosis compared with normal-weight patients. This may be attributed to hyperinsulinemia and dysregulation of adipokine levels associated with overweight and obesity. Here, we evaluate whether low levels of adiponectin and a greater level of insulin resistance are associated with breast cancer mortality and all-cause mortality. Patients and Methods We measured glucose, insulin, and adiponectin levels in fasting serum samples from 527 women enrolled in the Health, Eating, Activity, and Lifestyle (HEAL) Study, a multiethnic, prospective cohort study of women diagnosed with stage I-IIIA breast cancer. We evaluated the association between adiponectin and insulin and glucose levels (expressed as the Homeostatic Model Assessment [HOMA] score) represented as continuous measures and median split categories, along with breast cancer mortality and all-cause mortality, using Cox proportional hazards models. Results Increasing HOMA scores were associated with reduced breast cancer survival (hazard ratio [HR], 1.12; 95% CI, 1.05 to 1.20) and reduced all-cause survival (HR, 1.09; 95% CI, 1.02 to 1.15) after adjustment for possible confounders. Higher levels of adiponectin (above the median: 15.5 μg/mL) were associated with longer breast cancer survival (HR, 0.39; 95% CI, 0.15 to 0.95) after adjustment for covariates. A continuous measure of adiponectin was not associated with either breast cancer–specific or all-cause mortality. Conclusion Elevated HOMA scores and low levels of adiponectin, both associated with obesity, were associated with increased breast cancer mortality. To the best of our knowledge, this is the first demonstration of the association between low levels of adiponectin and increased breast cancer mortality in breast cancer survivors.

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Comment on: sarcopenia and serum biomarkers of oxidative stress after a 6-month physical activity intervention in women with metastatic breast cancer—results from the ABLE feasibility trial

Breast Cancer Research and Treatment ◽

10.1007/s10549-021-06502-2 ◽

2022 ◽

Author(s):

Irem Kirac Utku ◽

Umut Safer

Keyword(s):

Breast Cancer ◽

Oxidative Stress ◽

Physical Activity ◽

Metastatic Breast Cancer ◽

Physical Activity Intervention ◽

Metastatic Breast ◽

Serum Biomarkers ◽

Feasibility Trial ◽

Biomarkers Of Oxidative Stress

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Abstract 1277: Interaction of insulin-like growth factor-I and insulin resistance-related genetic variants with obesity and lifestyle factors on postmenopausal breast cancer risk

10.1158/1538-7445.am2017-1277 ◽

2017 ◽

Author(s):

Su Yon Jung ◽

Gloria Ho ◽

Thomas Rohan ◽

Howard Strickler ◽

Jennifer Bea ◽

...

Keyword(s):

Breast Cancer ◽

Insulin Resistance ◽

Growth Factor ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Genetic Variants ◽

Postmenopausal Breast Cancer ◽

Insulin Like Growth Factor ◽

Factor I ◽

Postmenopausal Breast Cancer Risk

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Metrics of Diabetes Risk Are Only Minimally Improved by Exercise Training in Postmenopausal Breast Cancer Survivors

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgz213 ◽

2019 ◽

Vol 105 (5) ◽

pp. e1958-e1966

Author(s):

Richard Viskochil ◽

Jennifer M Blankenship ◽

Grace Makari-Judson ◽

John Staudenmayer ◽

Patty S Freedson ◽

...

Keyword(s):

Breast Cancer ◽

Insulin Resistance ◽

Insulin Sensitivity ◽

Exercise Training ◽

Cancer Survivors ◽

Breast Cancer Survivors ◽

Postmenopausal Breast Cancer ◽

Sensitivity Index ◽

Supervised Exercise ◽

Glucose Ingestion

Abstract Context Insulin resistance is a risk factor for breast cancer recurrence. How exercise training changes fasting and postglucose insulin resistance in breast cancer survivors is unknown. Objective To evaluate exercise-induced changes in postglucose ingestion insulin concentrations, insulin resistance, and their associations with cancer-relevant biomarkers in breast cancer survivors. Setting The University of Massachusetts Kinesiology Department. Participants 15 postmenopausal breast cancer survivors not meeting the physical activity guidelines (150 min/week of exercise). Intervention A supervised 12-week aerobic exercise program (60 min/day, 3–4 days/week). Main outcome measures Postglucose ingestion insulin was determined by peak insulin and area under the insulin curve (iAUC) during a 5-sample oral glucose tolerance test. Insulin sensitivity was estimated from the Matsuda composite insulin sensitivity index (C-ISI). Changes in fitness and body composition were determined from submaximal VO2peak and dual energy X-ray absorptiometry. Results Participants averaged 156.8 ± 16.6 min/week of supervised exercise. Estimated VO2peak significantly increased (+2.8 ± 1.4 mL/kg/min, P < .05) and body weight significantly decreased (–1.1 ± 0.8 kg, P < .05) following the intervention. There were no differences in fasting insulin, iAUC, C-ISI, or peak insulin following the intervention. Insulin was only significantly lower 120 min following glucose consumption (68.8 ± 34.5 vs 56.2 ± 31.9 uU/mL, P < .05), and there was a significant interaction with past/present aromatase inhibitor (AI) use for peak insulin (–11.99 non-AI vs +13.91 AI uU/mL) and iAUC (-24.03 non-AI vs +32.73 AI uU/mL). Conclusions Exercise training had limited overall benefits on insulin concentrations following glucose ingestion in breast cancer survivors but was strongly influenced by AI use.

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Associations of clothing size, adiposity and weight change with risk of postmenopausal breast cancer in the UK Women’s Cohort Study (UKWCS)

BMJ Open ◽

10.1136/bmjopen-2018-022599 ◽

2018 ◽

Vol 8 (9) ◽

pp. e022599 ◽

Cited By ~ 3

Author(s):

Foong Ming Moy ◽

Darren C Greenwood ◽

Janet E Cade

Keyword(s):

Breast Cancer ◽

Cohort Study ◽

Weight Change ◽

Postmenopausal Breast Cancer ◽

Overweight And Obesity ◽

Breast Cancers ◽

Effective Measure ◽

Increased Risk ◽

The Uk ◽

Incident Cases

ObjectivesBreast cancer is associated with overweight and obesity after menopause. However, clothing size as a proxy of adiposity in predicting postmenopausal breast cancer is not widely studied. We aimed to explore the relationships between postmenopausal breast cancer risk with adipose indicators (including clothing sizes) and weight change over adulthood.DesignProspective cohort study.SettingEngland, Wales and Scotland.Participants17 781 postmenopausal women from the UK Women’s Cohort Study.Primary outcome measureIncident cases of malignant breast cancers (International Classification of Diseases (ICD) 9 code 174 and ICD 10 code C50).ResultsFrom 282 277 person-years follow-up, there were 946 incident breast cancer cases with an incidence rate of 3.35 per 1000 women. Body mass index (HR: 1.04; 95% CI: 1.02 to 1.07), blouse size (HR: 1.10; 1.03 to 1.18), waist circumference (HR: 1.07; 1.01 to 1.14) and skirt size (HR: 1.14;1.06 to 1.22) had positive associations with postmenopausal breast cancer after adjustment for potential confounders. Increased weight over adulthood (HR: 1.02; 1.01 to 1.03) was also associated with increased risk for postmenopausal breast cancer.ConclusionsBlouse and skirt sizes can be used as adipose indicators in predicting postmenopausal breast cancer. Maintaining healthy body weight over adulthood is an effective measure in the prevention of postmenopausal breast cancer.

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Obesity in Postmenopausal Breast Cancer Patients: It Is Time to Improve Actions for a Healthier Lifestyle. The Results of a Comparison Between Two Italian Regions With Different “Presumed” Lifestyles

Frontiers in Oncology ◽

10.3389/fonc.2021.769683 ◽

2021 ◽

Vol 11 ◽

Author(s):

Laura Cortesi ◽

Giulia Raffaella Galli ◽

Federica Domati ◽

Luana Conte ◽

Luigi Manca ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Size ◽

Southern Italy ◽

Postmenopausal Breast Cancer ◽

Overweight And Obesity ◽

Cancer Center ◽

Continuous Series ◽

Breast Cancer Patients ◽

Italian Regions ◽

Increased Risk

BackgroundAdult body fatness is a convincing risk factor for postmenopausal breast cancer. With the aim to compare the different breast cancer (BC) features in Northern and Southern Italy, we investigated the relationship between BMI and BC characteristic in two groups of patients referred in the Modena and Lecce breast units.Materials and MethodsA retrospective analysis of a continuous series of BC patients referred to the Città di Lecce Hospital and the Modena Cancer Center, from January 2019 to December 2020 was performed. We identified four groups of BMI at BC diagnosis: underweight, BMI <18.5 kg/m2; normal weight, BMI ≥ 18.5–24.9 kg/m2; overweight, BMI ≥ 25.0–29.9 kg/m2; obese, BMI ≥30.0 kg/m2. BC characteristics and clinical outcomes were analyzed by the Kolmogorov-Smirnov test and Mann-Whitney U test; categorical data were compared using Pearson’s chi-square test, and dicotomic data were compared by odds ratio.ResultsNine hundred seventy-seven BC patients were included in the analysis. Overall, 470 were from Modena and 507 from Lecce. No differences were observed in the mean age of BC patients of Modena (61,42) and Lecce (62,08). No statistical differences between the two populations were shown in terms of tumor characteristics and pathological stage. Conversely, a statistical difference of BMI between the BC patients coming from Modena and Lecce (25.87 and 27.81, respectively; p = 0.000001) was found. BC patients diagnosed in Lecce at age ≥70 years had higher median BMI compared with the ones from Modena (p = 0.000002). The increased BMI in this aged population was also associated to larger tumor size (p = 0.040).ConclusionThe rate of overweight and obesity was higher in BC women living in Southern Italy, despite the presumed nutrition according to the so-called Mediterranean type dietary pattern. Unexpectedly, an increased BMI rate and a relationship with larger tumor size were found in Southern BC patients aged ≥70 years. Our findings strongly support the need for promoting a healthier lifestyle model in Italy, with the aim of reducing the rate of the obesity and, consequently, the increased risk of BC.

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Higher Insulin Resistance and Adiposity in Postmenopausal Women With Breast Cancer Treated With Aromatase Inhibitors

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2018-02339 ◽

2019 ◽

Vol 104 (9) ◽

pp. 3670-3678 ◽

Cited By ~ 6

Author(s):

Fraser W Gibb ◽

J Michael Dixon ◽

Catriona Clarke ◽

Natalie Z Homer ◽

Abdullah M M Faqehi ◽

...

Keyword(s):

Breast Cancer ◽

Insulin Resistance ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Aromatase Inhibitors ◽

Glucose Tolerance Test ◽

Postmenopausal Breast Cancer ◽

Tolerance Test ◽

Oral Glucose ◽

Oral Glucose Tolerance

Abstract Context Aromatase deficiency causes obesity and insulin resistance in aromatase knockout mice and humans with rare mutations of the aromatase gene (CYP19). Aromatase inhibitors are a commonly prescribed therapy for postmenopausal breast cancer. Objective We hypothesized that aromatase inhibitors induce obesity and insulin resistance when used in treatment of breast cancer. Design Case-control study. Setting University teaching hospital. Participants Patients with postmenopausal breast cancer (n = 20) treated with aromatase inhibitors and 20 age-matched control subjects. Main outcome measures The primary outcome measure was insulin sensitivity index – Matsuda, derived from a 75-g oral glucose tolerance test. Body composition was assessed by dual energy x-ray absorptiometry and biopsy specimens of subcutaneous adipose tissue obtained for assessment of mRNA transcript levels. Data are reported as mean ± SEM (patients receiving inhibitors vs control group, respectively). Results Aromatase inhibitor therapy was associated with significantly lower insulin sensitivity (5.15 ± 0.45 vs 6.80 ± 0.64; P = 0.041), higher peak insulin concentration after oral glucose tolerance test (693.4 ± 78.6 vs 527.6 ± 85.5 pmol/L; P = 0.035), greater percentage of body fat (38.4% ± 1.0% vs 34.6% ± 1.3%; P = 0.026), and higher plasma leptin concentration (23.5 ± 2.8 vs 15.5 ± 2.3 ng/mL; P = 0.035). Conclusion Women who received aromatase inhibitors for postmenopausal breast cancer had greater percentage body fat and insulin resistance compared with control subjects with no history of breast cancer.

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Vitamin D mitigates the adverse effects of obesity on breast cancer in mice

Endocrine Related Cancer ◽

10.1530/erc-15-0557 ◽

2016 ◽

Vol 23 (4) ◽

pp. 251-264 ◽

Cited By ~ 23

Author(s):

Srilatha Swami ◽

Aruna V Krishnan ◽

Jasmaine Williams ◽

Abhishek Aggarwal ◽

Megan A Albertelli ◽

...

Keyword(s):

Breast Cancer ◽

Insulin Resistance ◽

Vitamin D ◽

Adverse Effects ◽

Postmenopausal Breast Cancer ◽

Dietary Vitamin ◽

Obese Mice ◽

Established Risk Factor ◽

Estrogen Synthesis ◽

Dietary Vitamin D

AbstractObesity is an established risk factor for postmenopausal breast cancer (BCa), insulin resistance, and vitamin D deficiency, and all contribute to increased synthesis of mammary estrogens, the drivers of estrogen receptor-positive (ER+) BCa growth. As both dietary vitamin D and calcitriol treatments inhibit breast estrogen synthesis and signaling, we hypothesized that vitamin D would be especially beneficial in mitigating the adverse effects of obesity on ER+BCa. To assess whether obesity exerted adverse effects on BCa growth and whether vitamin D compounds could reduce these unfavorable effects, we employed a diet-induced obesity (DIO) model in ovariectomized C57BL/6 mice. Breast tumor cells originally from syngeneicMmtv-Wnt1transgenic mice were then implanted into the mammary fat pads of lean and obese mice. DIO accelerated the initiation and progression of the mammary tumors. Treatments with either calcitriol or dietary vitamin D reduced the adverse effects of obesity causing a delay in tumor appearance and inhibiting continued tumor growth. Beneficial actions of treatments with vitamin D or calcitriol on BCa and surrounding adipose tissue included repressedEsr1, aromatase, andCox2expression; decreased tumor-derived estrogen and PGE2; reduced expression of leptin receptors; and increased adiponectin receptors. We demonstrate that vitamin D treatments decreased insulin resistance, reduced leptin, and increased adiponectin signaling and also regulated the LKB1/AMPK pathway contributing to an overall decrease in local estrogen synthesis in the obese mice. We conclude that calcitriol and dietary vitamin D, acting by multiple interrelated pathways, mitigate obesity-enhanced BCa growth in a postmenopausal setting.

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