The present retrospective study was designed to examine the relationship between type 2 diabetes, body mass index (BMI), and survival in a large group of patients with early-stage breast cancer. Diabetes and obesity, which share overlapping etiologies, have been reported to be associated with poorer breast cancer outcomes in some, but not all, studies. The study included 6,106 patients treated at M.D. Anderson Cancer Center from 1996 to 2005. The patients were placed into diabetic and non-diabetic groups and into three BMI classes: normal or underweight (BMI < 25), overweight (BMI 25-30), and obese (BMI ≥ 30). 476 (7.8%) of the study group had diabetes, 40% were normal or underweight, 31% were overweight, and 29% were obese. The median age was 52 years (range: 19 to 91). 93% had stage I-II disease and 7% had stage III. 77% had hormone-receptor positive tumors, 18% HER2 were overexpressing. Recurrence-free survival and overall survival were estimated by the Kaplan-Meier product and compared between groups using the log-rank test. Cox proportional hazards models were used to conduct multivariate analysis. By chi-squared tests, diabetes was found to be associated with increasing age, breast cancer stage, and BMI; and higher BMI was associated with increasing age, stage, grade, and diabetes. After a median follow-up period of 5.4 years, 488 breast cancer recurrences and 921 deaths had taken place. Recurrence-free survival and overall survival were found to be significantly worse in diabetic compared to non-diabetic patients (p < 0.001 and p < 0.001, respectively), and in the obese compared to the normal or underweight group (p < 0.001 and p = 0.002, respectively). Diabetic patients had decreased recurrence-free survival (hazard ratio (HR) = 1.22; 95% confidence interval (CI) = 0.99-1.50; p = 0.065) and overall survival (HR = 1.40; 95% CI = 1.11 - 1.78; p = 0.005) after adjusting for diabetic status, BMI, age, stage, grade, and hormone receptor status. Using the same model, obese compared to normal or underweight patients had lower recurrence-free survival (HR = 1.15; 955 CI = 0.99 - 1.33; p = 0.065) and overall survival (HR = 1.26; 955 CI = 1.06-1.50; p = 0.010). The authors conclude that diabetes and obesity each were associated with a significant reduction in overall survival, as well as a borderline significant decrease in recurrence-free survival, after adjustment for diabetes status, BMI, age, stage, grade, and hormone receptor status.

The current retrospective study was designed to examine the influence of body mass index (BMI) on outcomes of women with HER2 overexpressing breast cancer treated with trastuzumab (Herceptin). Obesity and HER2 overexpression are known to be linked with poor prognosis in breast cancer patients. Recent studies have suggested the existence of functional crosstalk between HER2 and leptin, a hormone correlated with excess fat. In particular, stimulation with leptin can transactivate HER2 and activate its downstream signaling. Chronic exposure to leptin increases HER2 stability in both the presence or absence of Herceptin. The current study included 155 patients with HER2-positive status treated with Herceptin for early stage or metastatic breast cancer during the period 2003 to 2008. Patients were divided into normal, overweight, and obese categories according to BMI, following WHO guidelines. Overall survival and time to progression were estimated by the Kaplan-Meier method and comparisons were made using the log-rank test. One hundred and three 103 patients were treated with adjuvant Herceptin. Of the overall study group, 12.5% relapsed during the study period. Among the relapsed patients (in which breast cancer progressed), 31% were overweight and 23% were obese. Also within this subgroup, overall survival and time to progression decreased with increasing BMI: the median overall survival for normal weight patients was 40 months, whereas it was 36.5 months for overweight and 31 months for obese patients. Similarly, median time to progression was 11 months for normal weight patients, whereas it was eight months for overweight and five months for obese patients (p=0.0351). Fifty-two patients received chemotherapy plus Herceptin for metastatic disease. In this population, 33% of the patients were overweight and 15% were obese; median overall survival was 65 months and time to progression 10.5 months. Again among this subgroup, decreased overall survival and time to progression were found with increasing BMI: median overall survival for normal weight women was 67 months, whereas it was 54 for overweight and 39 for obese patients (p=0.0010); median time to progression was 12, 7.5, and 7 months, respectively (p=0.0442). Reduced survival associated with increasing BMI was also found when the overall population was studied according to hormone receptor and menopausal status. The authors conclude that obesity predicts worse outcomes in HER2-positive patients. Furthermore, the results validate previous laboratory studies suggesting that leptin can impair response to Herceptin in breast cancer cells.

The present pilot study was designed to determine the effect of a structured weight loss program on blood and breast tissue cancer risk biomarkers on overweight postmenopausal women. The degree of baseline weight loss or fat loss required to reduce breast cancer risk in overweight women has not been determined. Postmenopausal women were eligible for the study if their body mass index (BMI) exceeded 25 kg/m2, they were not taking hormone replacement therapy (HRT), they met high risk criteria (either five-year Gail > 1.7%, prior contralateral breast cancer, or precancerous biopsy), and had breast tissue (harvested by random periareolar fine needle aspiration (RPFNA)) indicating evidence of hyperplasia and Ki-67 > 1.5%. The primary endpoint of the study initially was to determine the proportion of women with at least 5% weight loss and the effect of such loss on Ki-67. However, due to a low proportion of women with Ki-67, minimum eligibility criteria were changed to cytomorphology and a frozen aliquot. The women underwent a six-month weight loss intervention which included a reduced energy diet, physical activity, and weekly meetings for behavioral strategies with other high risk women. Body composition (DEXA), fasting serum insulin, glucose, adiponectin, leptin, high sensitivity CRP, Il6, prolactin, SHBG, estradiol and testosterone were assessed before and after the intervention. Sixty-eight 68 women were screened by RPFNA, with 11 (16%) exhibiting Ki-67 > 1.5%. Twenty-seven women enrolled (seven with Ki-67 > 1.5%); but one was declared ineligible and two dropped out prior to starting the diet. For the remaining 26 subjects, median weight, BMI, and percent body fat at baseline were 95 kg, 34.2 kg/m2, and 51%, respectively. Imputing no loss for the two subjects who dropped out, 20/26 had weight loss of at least 5%. For 24 biomarker evaluable subjects, median change in weight was -9.9 kg (10.9% relative) and % fat was -3.8% (-7.7% relative). Median baseline Ki-67 was 0.4% and off study 0.2% for all; and 2.2% and 0.4 % for those with baseline Ki-67 > 1.5%. Cytologic atypia was present in 10 of the 24 participants at baseline and four of the 24 at six months (p = 0.07, McNemar). Serum breast biomarkers that showed significant improvement included adiponectin (p = 0.0015), and leptin, CRP, SHBG, and estradiol (all p < 0.001). The authors conclude that the study achieved the weight loss goal of at least 5% (most lost exceeded 10%), with improvement in multiple tissue-based risk biomarkers.

The current study was designed to investigate the relationship between type 2 diabetes and breast cancer prognosis. Diabetes increasingly has been reported to be associated with poorer outcomes among those with breast cancer. It has been estimated that 16% to 20% of breast cancer patients have diabetes and up to 30% are undiagnosed. The study included 3,003 early stage breast cancer survivors enrolled in a large prospective dietary intervention trial. The women were followed for a median of seven years. Stored red blood cells collected at baseline were used to measure HbA1c using high-performance liquid chromatography. Participants with HbA1c levels of 7.0% and above were classified as having diabetes, HbA1c levels of 6.5% to 6.9% were considered high-risk for diabetes, and HbA1c levels of 6.4% and lower served as the non-diabetic reference category. HbA1c levels of 6.5% and above were found to be more likely to be associated with several sociodemographic (less educated, older age, non-white ethnicity) and prognostic (more advanced breast cancer at diagnosis, obesity) factors. Obese women comprised 70% of the diabetes. HbA1c was found to be significantly associated with worse overall survival (p for trend < 0.0001). The risk of all-cause mortality was twice as high among women with diabetes compared to those with HbA1c levels of 6.4% or lower (hazard ratio (HR) = 2.39; 95% confidence interval (CI) = 1.59-3.59), after adjusting for confounders. On the other hand, the relationship between diabetes and disease-free survival did not reach statistical significance (HR = 1.30; 95% CI = 0.79-2.05), although the results were suggestive of worsening prognosis with increasing HbA1c levels. The authors comment that there is significant under-reporting of diabetes in obese breast cancer survivors. They conclude that diabetes is significantly associated with poorer overall survival and suggestive of worse disease free survival.