Breast Cancer Lymphedema: Role of Insulin Resistance/FOXC2

Institution: Stanford University
Investigator(s): Stanley Rockson, M.D. -
Award Cycle: 2005 (Cycle 11) Grant #: 11IB-0172 Award: $234,071
Award Type: IDEA
Research Priorities
Etiology and Prevention>Etiology: the role of environment and lifestyle

Initial Award Abstract (2005)
Introduction: Breast cancer surgery and radiation therapy is life-saving, but can leave survivors at risk to develop chronic swelling, pain, and loss mobility in the arm adjacent to the prior cancer. This condition is called `lymphedema'. When it occurs, it has been shown to have a profound impact on the function and quality of life of affected individuals. It is difficult to identify the patients at highest risk for lymphedema and current treatment options are very limited and not highly successful. In order to ensure quality-of-life and high function in breast cancer survivors, we must better understand the mechanisms in the body that lead to the development of lymphedema.

Hypotheses: Since 15-25% of breast cancer survivors develop lymphedema, and this risk does not appear to be strongly linked to the extent of original disease or surgery, it is likely that hereditary factors (genetic variation) play a strong role. While these factors have not yet been identified, there is a suggestion that a particular gene, whose structure varies in the general population, may be responsible. This gene is of particular interest, because it also affects the way in which the body handles sugar, starch and fat. When the gene is underactive, the indivual is predisposed to resistance to the action of insulin. Insulin resistance has been linked to breast cancer in general, and may be responsible, in part for the risk of lymphedema and for the changes in the lymphedema arm over time. If we can identify that lymphedema-stricken survivors are more insulin resistant than women without swelling, this will provide avenues to treat lymphedema with medication, currently unavailable. Also, if the insulin resistance/lymphedema gene is found to vary in the lymphedema patients, it will provide avenues to create screening and prevention strategies in future patients who face breast cancer treatment.

Methodology: Breast cancer survivors who are at least 4 years beyond initial treatment will be studied. Thirty women with arm swelling will be compared with age-matched women who lack swelling. Blood studies will be performed in a clinical research outpatient setting. These will allow determination of insulin sensitivity and glucose tolerance. Blood will also be obtained for DNA analysis of the gene in question. The results will be analyzed with reference to whether the individual does or does not have arm swelling.

Innovative elements: Few studies have been performed that provide insight the mechanisms of this breast cancer complication. The risk of lymphedema is a feared outcome of successful treatment of breast cancer, yet we have minimal tools and technology to predict risk, prevent swelling, or treat full-blown lymphedema. If these studies are successful, they will provide much-needed advances in each of these relevant areas.

Advocacy involvement: Lay advocacy groups both regionally and nationally have identified breast cancer lymphedema as an area of significant concern. Our research group has worked closely with advocacy groups and will continue to do so. We will continue to seek input from this constituency and will rely upon advocacy organizations to assist us in identifying breast cancer survivors who wish to participate in these research endeavors and potentially change the face of breast cancer care in the future.

Final Report (2008)
Lymphedema of the arm is a common, life-altering and often debilitating consequence of the surgical and radiotherapeutic interventions for breast cancer. Factors that predispose to this complication, which occurs in an estimated 15-25% of breast cancer survivors, are not well-defined but, among the systemic factors associated with lymphedema risk, hypertension and obesity are consistently identified. In addition, expression of FOXC2, a gene associated with insulin resistance, is also implicated to play a role in lymphatic development. Therefore, we have postulated that risk of breast cancer-associated lymphedema (BCL) may be associated with presence of relative insulin resistance, and that the unifying factor may be relative expression of FOXC2 in the at-risk individuals.

We studied insulin sensitivity in 23 prospectively identified breast cancer survivors who underwent ALND with and without BCL. Ratios of limb volume were calculated with the truncated cone approximation of limb circumference. All patients underwent bioimpedance measurements. The presence of lymphedema was defined as a ratio >1.1 and was confirmed by measuring the bioimpedance ratios (BR) in each patient. 13 patients had lymphedema (BCL+) and 10 did not (BCL-). The groups were matched for age, BMI and elapsed time since ALND (axillary lymph node dissection). Insulin sensitivity was assessed by quantitation of steady state plasma glucose (SSPG) during octreotide infusion and further confirmed with oral glucose tolerance test (OGTT). These aims were successfully completed. We also collected and stored peripheral blood for sequence analysis of the FOXC2 gene; this portion of the study remains uncompleted.

The largest barrier to successful completion of the study was establishing adequate venous access to complete the metabolic study: inability to complete the necessary venipuncture resulted in unsuccessful or incomplete enrollment of many subjects. Metabolic studies revealed that, with high statistical significance, the lymphedema-positive breast cancer survivors were much more hyperglycemic (p<0.007) after a glucose load, and that insulin sensitivity measures were inversely correlated with the lymphedema risk (r=0.7): thus increasing insulin sensitivity predicted increasing risk of edema accumulation in the affected arm.

These results were unexpected and highly novel. They suggest that prevailing elevated levels of circulating insulin may aid in the lymphatic repair response, conferring relative protection against the development of lymphedema. We propose to pursue these relationships both in animal models of lymphedema and, clinically, in more robust studies of insulin, kinetics in response to glucose challenge.