NEW YORK (Reuters Health) - Poor breast cancer outcomes in women with diabetes and obesity are linked to hyperinsulinemia, new research suggests.
The research is reported in five separate papers, all published online November 29 in the Journal of Clinical Oncology.
The findings show that diabetes reduces breast cancer survival, while obesity seems to interfere with chemotherapy. And undiagnosed hyperglycemia more than doubles mortality within 10 years. Even biomarkers of insulin production and insulin resistance are strongly tied to shortened survival.
But patients are likely to benefit from "dietary interventions, increased physical activity, and insulin-lowering drugs, such as metformin," Drs. Andrea DeCensi and Alessandra Gennari from Galliera Hospital in Genoa, Italy, write in an editorial.
They offer advice for physicians treating breast cancer patients: Measure waist circumference to detect visceral obesity (>/= 80 cm in women) and HOMA index to determine insulin resistance, so that lifestyle interventions can be tailored to the patient.
Also, they say, "in patients with breast cancer who have overt diabetes or glucose intolerance, metformin should be regarded as the antidiabetic drug of choice." Metformin has been linked to lower cancer-specific mortality and a better response to chemotherapy.
One study, a meta-analysis by Johns Hopkins researchers led by Dr. Kimberly S. Peairs, involved nearly 90,000 patients enrolled in six studies; 8-20% had diabetes. Patients had been diagnosed with breast cancer between 1985 and 2002, and the studies were published between 2001 and 2009.
Results showed that diabetics had a 49% increased risk for all-cause mortality. "This finding was consistent across different populations, was generally independent of possible confounding variables, and was robust even after accounting for possible publication bias," the authors note.
One paper in the meta-analysis indicated that diabetics treated with chemotherapy were more likely to be hospitalized for toxicity, infection, neutropenia, or anemia. That likely explains the modified treatment regimens observed among diabetics, including less use of adjuvant chemotherapy and radiation therapy.
New research: Undiagnosed diabetes even more dangerous
Chronic hyperglycemia in the absence of a diabetes diagnosis also portends poorer survival after an early-stage breast cancer diagnosis, according to investigators with the Moores Cancer Center at the University of California, San Diego in La Jolla.
Dr. John P. Pierce and colleagues measured hemoglobin (Hb)A1C in archived blood samples from 3003 survivors of early breast cancer.
HbA1C levels were between 6.5% and 6.9% in 94 women and 7% or higher in 91. Only a quarter of those with an elevated HbA1C knew they had diabetes.
During a median follow-up of 10 years, 414 women died: 13.1% of those with an HbA1C < 6.5%; 19.1% in the middle HbA1C category and 30.8% in the highest category.
Compared with an HbA1C < 6.5%, a level of 7% or higher had a hazard ratio of 2.35, after controlling for stage, grade, age, ethnicity, education, physical activity, and physical health.
If these findings are confirmed, clinicians may want to measure HbA1C in their breast cancer patients, Dr. Pierce and his associates conclude.
C-peptide, low adiponectin, and obesity also prognostic
In another study of a similar population, high fasting C-peptide levels -- a marker of insulin production -- more than doubled the risk of breast cancer mortality over a median period of six years.
Dr. Melinda L. Irwin, from Yale School of Public Health, New Haven, Connecticut, and her team studied 604 women whose fasting C-peptide levels were measured three years after their diagnosis. Fifty-eight subjects had type 2 diabetes, and 175 had C-peptide levels above 2.5 ng/mL (levels between 0.5 and 2.0 ng/mL are considered healthy).
Sixty-seven women died, including 33 who died of breast cancer.
Compared to nondiabetic women with C-peptide < 1.7 ng/mL, the adjusted HR for breast cancer death among nondiabetics with C-peptide > 2.5 ng/mL was 2.39 (adjusted for age, BMI, disease stage, estrogen receptor status, adjuvant treatment, and race/site). Compared to the same reference group, diabetics had an aHR of 2.83.
Dr. Irwin and colleagues note that the relationship between C-peptide and breast cancer mortality was even stronger for low-weight women (BMI < 25 kg/m2), higher stage of disease, and estrogen receptor-positive tumors.
A separate team, headed by Dr. Catherine Duggan at the Fred Hutchinson Cancer Research Center in Seattle, analyzed adiponectin levels and insulin resistance among 527 women diagnosed with breast cancer in stages I to III.
Adiponectin is inversely related to obesity and insulin resistance -- and women with adiponectin levels above the median had better cancer-specific survival.
Increasing insulin resistance, determined by the HOMA index, was linked to lower all-cause and breast cancer-specific survival.
Meanwhile, Danish researchers showed for the first time that a high BMI seems to reduce the effectiveness of adjuvant treatments. Led by Dr. Marianne Ewertz at Odense University Hospital, they analyzed data on 18,967 patients diagnosed with early-stage breast cancer between 1977 and 2006.
Compared to a BMI < 25 kg/m2, a BMI of 30 or higher was associated with more advanced disease at diagnosis and a higher mortality rate at 30 years (57.2% vs 46.4%; aHR 1.38, p = 0.003). Distant metastases at 10 years were also more common in obese subjects.
"After 10 years," Dr. Ewertz team says, "both chemotherapy and endocrine therapy seemed to be less effective in patients with BMIs of 30 kg/m2 or greater," with aHRs for mortality of 1.57-1.77.
In their editorial, Drs. DeCensi and Gennari suggest that a link between cancer and insulin is "biologically plausible," since insulin stimulates DNA synthesis and cell proliferation. Insulin may also cross-activate insulin-like growth factor receptors, which regulate cell growth, differentiation, apoptosis, and transformation.
In a separate editorial, Dr. Frank A. Sinicrope from Mayo Clinic in Rochester, Minnesota, and Dr. Andrew J. Dannenberg from the Weill Cornell Cancer Center in New York warn that "obesity has the potential to diminish important advances that have been made in the fight against breast and other cancers."
They blame obesity's effect on increasing levels of proinflammatory cytokines, which they say can be reduced by weight loss.
By Karla Gale
Sources:
http://link.reuters.com/hus97q
http://link.reuters.com/tes97q
http://link.reuters.com/ses97q
http://link.reuters.com/res97q
http://link.reuters.com/nes97q6
http://link.reuters.com/mus97q
http://link.reuters.com/kus97q
J Clin Oncol 2010.
Last Updated: 2010-12-02 19:59:29 -0400 (Reuters Health)
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