In this study, we observed that adiponectin levels measured from serum collected from breast cancer survivors approximately 30 months post-diagnosis and above the median in our study sample were associated with a 61% decreased risk of breast cancer–associated death. To the best of our knowledge, this is the first demonstration of an association between high levels of adiponectin and improved breast cancer prognosis.
Additionally we found that elevated HOMA scores were significantly associated with both breast cancer mortality and all-cause-mortality in a model adjusted for age, BMI, race/site, tamoxifen use at time of blood draw, and levels of leptin, estradiol, and IGF-1. However, unlike Goodwin et al,13
who reported an HR of 3.3 for risk of death in patients with insulin levels in the highest quartile compared with the lowest, we found no association with outcome when we analyzed HOMA scores categorized as quartiles for all-cause mortality. Our means for insulin were higher and had a wider range than those reported by Goodwin et al25
(66.9 pmol/mL; range, 8.3 to 676.4 pmol/L v
8.0 to 340 pmol/L), and the HEAL participants had a higher mean BMI (27.3 kg/m2 v
Given the small number of events, we postulate that we have insufficient power to analyze the association with overall mortality by quartiles. For breast cancer mortality, we observed that patients with HOMA levels in the third quartile had a significantly elevated risk of death compared with patients in the lowest quartile. However, the CIs were wide because of the small number of events.
While HOMA scores were associated with all-cause mortality, adiponectin levels were not. However, when we restricted the analysis to participants with glucose levels < 126 mg/dL, high levels of adiponectin were statistically significantly associated with improved prognosis for all-cause mortality (HR, 0.51; 95% CI, 0.28 to 0.91). The lack of association between HOMA scores and outcome in women with glucose levels ≤ 126 mg/dL may be due to lower levels of insulin in this group compared with those in the high-glucose group who are more likely to have a worse prognosis associated with elevated insulin levels. A recent paper examining severe insulin resistance and hyperinsulinemia in a non-obese diabetic mouse model demonstrated accelerated mammary gland development and breast cancer progression independent of obesity and inflammation, mediated via insulin, insulin receptor/IGF-1 receptor, and the PI3K/Akt pathway,26
supporting the tumor-promoting effect of elevated circulating insulin levels.
As we hypothesized, there was an association between HOMA scores and all-cause mortality in women with a BMI > 25 kg/m2. Additionally, HOMA was associated with all-cause mortality and breast cancer mortality in participants diagnosed with regionally invasive and ER-positive breast cancer. Adiponectin was not associated with outcome in any of these subgroups.
have demonstrated that hyperinsulinemia is associated with poor prognosis in women diagnosed with breast cancer. Insulin can stimulate cell proliferation, possibly via signaling through its receptor,27
in both normal and malignant breast cell lines.28
In addition, insulin downregulates IGF binding proteins and sex hormone–binding globulin, thus increasing bioavailable mitogens such as sex steroid hormones and IGF-1 with accompanying downstream cellular effects.29–32
Our observation of a greater association of mortality with HOMA, a marker of insulin resistance and long-term hyperinsulinemia, compared with insulin concentrations, may be because a single measure of insulin is an incomplete marker of long-term insulin production and may not reflect diurnal variation. In support of this, an earlier report from our study found that elevated C-peptide concentrations were negatively associated with breast cancer survival (Irwin et al, submitted for publication).
Epidemiologic studies support a significant inverse association between adiponectin and breast cancer that is present even with adjustment for adiposity.16–19,34,35
Adiponectin is secreted from adipose tissue and may play a key role in regulating energy intake and expenditure.36
Levels are inversely correlated with BMI and adipose tissue mass15,37,38
and are downregulated in overweight/obesity.37,39–43
Comparable to results from another study,44
our results demonstrated that adiponectin is inversely associated with sex steroid levels, which have positive associations with progression of breast cancer. Adiponectin has effects on cell proliferation and cytokine production,45
and experiments both in vitro and in animal models suggest an interaction between adiponectin and ERs.46–49
Adiponectin is secreted primarily by adipocytes, which may explain the attenuation of the relationship between adiponectin and breast cancer mortality, after adjustment for central obesity (waist-to-hip ratio).
Our study has several strengths. It is a population-based, multiethnic cohort of women with incident breast cancer; thus, results can be generalized to patients seen in routine clinical practice. Blood was collected after primary treatment was completed and therefore reflects ongoing host factors that can affect prognosis. We were able to adjust results for multiple demographic, anthropometric, tumor, and treatment characteristics, which improved validity.
Our study also has several limitations. We collected only one fasting blood sample and therefore cannot completely characterize the women's exposure to insulin or adiponectin. However, other studies indicate that a single fasting blood measure of these analytes is highly reproducible in postmenopausal women. We could not assess the effect of change in insulin resistance or adiponectin, which would require testing interventions to change these analytes such as weight loss, physical activity, or medications to alter insulin resistance. Finally, we were unable to assess risk in specific subgroups, including ER-negative disease, because of small numbers.
Insulin levels can be successfully lowered via behavioral and lifestyle interventions, such as increasing physical activity levels. In a cohort of breast cancer survivors, a mixed strength and endurance exercise intervention in obese, sedentary breast cancer survivors resulted in significant reductions in circulating insulin levels, and a concomitant nonsignificant improvement in HOMA scores.50
It is unclear whether alterations in adiponectin levels could be achieved by similar lifestyle interventions.51
A recent study of overweight breast cancer survivors failed to demonstrate any significant changes in adiponectin levels after a 16-week randomized controlled exercise intervention. However, there were also no significant changes in either weight or body composition in this study.52
Metformin acts through the AMPK/mTOR/S6K1 axis,53
and observational cohort studies suggest that metformin is associated with reduced risk of cancer in patients with type 2 diabetes.54–56
Diabetic breast cancer patients using metformin, an insulin-lowering medication, experience a higher rate of pathologic complete response to neoadjuvant chemotherapy than those using other diabetic treatments (odds ratio, 2.95; P
This has prompted clinical trials of metformin, including a trial of neoadjuvant chemotherapy and trastuzumab with or without metformin in women diagnosed with HER2-positive primary breast cancer.58
Two other trials are planned: one that will evaluate the effects of metformin on breast cancer outcomes59
and a second presurgical, randomized, phase II biomarker trial to evaluate the activity of metformin on tumor cell proliferation in breast cancer patients.60
Our study confirms the importance of hyperinsulinemia as an independent risk factor for poor prognosis in women with breast cancer and the association between low levels of adiponectin and shorter breast cancer survival. Randomized controlled trials involving lifestyle interventions, such as physical activity or weight loss, have resulted in reductions in insulin among women with breast cancer and may represent an important approach for improving prognosis in women via reductions in hyperinsulinemia.