Ana Elisa Lohmann

Association of Obesity-Related Metabolic Disruptions With Cancer Risk and Outcome.

Over the past 40 years, the prevalence of obesity has increased epidemically worldwide, which raises significant concerns regarding public health and the associated economic burden. Obesity is a major risk factor for several conditions including cardiovascular disease and type 2 diabetes, and recent evidence suggests that obesity negatively affects cancer risk and outcome. The relationship between obesity and cancer is complex and involves multiple factors both at the systemic and cellular level. Indeed, disruptions in insulin metabolism, adipokines, inflammation, and sex hormones all contribute to the adverse effects of obesity in cancer development and progression. The focus of this review will be the impact of these systemic obesity-related factors on cancer biology, incidence, and outcome. Potential therapeutic interventions and current clinical trials targeting obesity and its associated factors will also be discussed.

Hype versus Hope: Metformin and Vitamin D as Anticancer Agents

There has been increasing interest in the use of metformin and vitamin D to reduce cancer risk and improve outcomes. Metformin, an oral antidiabetic drug, improves insulin resistance and has been associated with reduced cancer incidence and cancer mortality. Low levels of vitamin D have also been associated with increased cancer risk, mainly in retrospective studies, and it has been suggested that vitamin D supplementation might play a role in cancer prevention. Preclinical data provide a biologic rationale for these associations; however, the human data arise predominantly from observational studies and caution is needed in their translation into clinical practice. This is because of the recognized limitations of observational studies, such as time-related survival biases, selection and referral biases, short follow-up, and the presence of confounding factors that can lead to spurious or inaccurate findings. Combined examination of associations with cancer risk and outcome (occurring when exposure in a population that does not yet have cancer is analyzed in relation to cancer death) may yield results that are difficult to interpret. Finally, associations across all cancers may differ from those in specific cancer types. These shortcomings can be overcome in properly designed and adequately powered prospective randomized trials; however, such trials are both expensive and time consuming. We review the literature examining the associations of metformin and vitamin D with cancer, discussing weakness and strengths and making recommendations for further research and clinical practice.

Association of Metabolic, Inflammatory, and Tumor Markers With Circulating Tumor Cells in Metastatic Breast Cancer

Abstract Background Circulating tumor cells (CTCs) are associated with worse prognosis in metastatic breast cancer (BC). We evaluated the association of metabolic, inflammatory, and tumor markers with CTCs in women with metastatic BC before commencing a new systemic therapy. Methods Ninety-six patients with newly diagnosed or progressing metastatic BC without current diabetes or use of anti-inflammatory agents were recruited from four Ontario hospitals. Women provided fasting blood for measurement of metabolic, inflammatory, and tumor markers and CTCs. CTCs were assayed within 72 hours of collection using CellSearch. Other blood was frozen at –80°C, and assays were performed in a single batch. Associations between CTC counts with study factors were evaluated using Spearman correlation, and the chi-square or Fisher exact test. All statistical tests were two-sided and P value ≤ .05 was considered statistically significant. Results The median age was 60.5 years; 90.6% were postmenopausal. The cohort included hormone receptor–positive (87.5%), HER2–positive (15.6%), and triple-negative (10.4%) BCs. Patients were starting firstline (35.5%), second-line (26.0%), or third-or-later-line therapy (38.5%). CTC counts (per 7.5 mL of blood) ranged from 0 to 1238 (median 2); an elevated CTC count, defined as five or more CTCs, was detected in 42 (43.8%) patients. Those with liver metastases (vs not) more frequently had an elevated CTC count (59.0% vs 33.3%, P = .02). CTCs were significantly associated with C-reactive protein (R = .22, P = .02), interleukin (IL)-6 (R = .25, P = .01), IL-8 (R = .38, P = .0001), plasminogen activator inhibitor 1 (R = .31, P = .001), carcinoembryonic antigen (R = .31, P = .002), and cancer antigen 15-3 (R = .40, P = .0001) and inversely associated with body mass index (R = –.23, P = .02) and leptin (R = –.26, P = .01). Conclusions CTC counts were positively associated with tumor and inflammatory markers and inversely associated with some metabolic markers, potentially reflecting tumor burden and cachexia.

Moving forward with obesity research in breast cancer

Obesity has been associated with higher incidence of both postmenopausal, primarily receptor positive, and premenopausal triple negative breast cancer (BC) risk [1]. Secondary analysis of the Womens Health Initiative clinical trial showed that obese versus non-obese postmenopausal women have a higher overall risk of BC (hazard ratio [HR], 1.58; 95% confidence interval (CI), 1.40e1.79) and more advanced stage, larger tumor size (HR, 2.12; 95% CI, 1.67e2.69) than normal weight women [2]. Furthermore, a recent meta-analysis confirmed an increased risk of all-cause mortality for BC patients with body mass index (BMI) > 30mg/m2 at BC diagnosis versus normal weight patients (relative risk (RR), 1.41; 95% CI, 1.29e1.53) [3]. The articles by Sahin et al. and Karatas et al. that accompany this editorial investigated prognosis in obese women [4,5]. Sahin et al. studied 3637 BC patients and reported worse overall survival (OS) in obese women (BMI 30 kg/m2) in the population as whole and in certain subgroups, premenopausal obese patients with triple negative BC or luminal-like subtype, but not the postmenopausal subgroup of women. The latter finding is not consistent with previous reports (e.g. Dobbins et al. [1]); because the qualitative patterns of risk were similar in preand postmenopausal women, lower power due to a smaller number of events in postmenopausal women may have contributed to the negative findings in this group. Sahin et al. also showed that, amongst premenopausal women who were obese, there was a higher proportion of triple negative and HER-2 like BCs than was seen in normal weight women which is consistent with prior report of associations of obesity with BC risk [1]. Obese premenopausal women had higher tumor stages (T3-T4), tumor grade (III) and advanced clinical stage than non-obese women; similar associations were not seen in postmenopausal women. In the article by Karatas et al., obese and overweight women, BMI 25 kg/m2, had lower complete pathologic response (pCR) rates after neoadjuvant chemotherapy for BC than underweight and normal women. In addition, obese and overweight women had significantly shorter relapse-free survival and OS5. These results are consistent with previous reports [6]. In both of these manuscripts, BMI was treated as a categorical variable; power would have been greater if BMI was used as a continuous variablemodelling it linearly or non-linearly, in keeping with prior reports. Although it is well recognized that obesity is associated with poor BC outcome in observational studies, these associations are not known to be causal and they could be related to a potential bias or cofounding, such as, suboptimal chemotherapy dosing (ie:

Abstract P1-09-02: BMI and metabolic factors in long-term breast cancer survivors: Changes from diagnosis and comparison to non-breast cancer controls

Background: The metabolic syndrome is associated with poor breast cancer (BC) outcome. We evaluated changes from diagnosis in metabolic factors and BMI in long-term survivors and compared their status at long-term follow-up (LTFU) to that of age-matched women with no history of BC. Methods: A total of 535 women with early breast cancer were enrolled between 1989 and 1996 and followed prospectively. From 2005 to 2007, those alive without distant recurrence were re-contacted to participate in a long-term followed-up study and 285 agreed. A control group of 167 age-matched women without cancer history was recruited from women presenting for screening mammograms. Mean changes in metabolic factors from diagnosis to long-term follow-up were assessed with paired t-tests. In spite of matching, controls were younger and had higher income than survivors and the comparison to controls was made using age-adjusted regression models. Variables were transformed to normality before statistical testing. Results: With a median follow-up of 12.5 years, BC survivors gained on average 2.35 kg and BMI, waist and hip circumference, waist-hip ratio, glucose, insulin, HOMA, total cholesterol and its components (but not triglycerides) increased significantly. After age adjustment, waist circumference, glucose, HOMA and total triglycerides were significantly higher in BC survivors compared to controls Despite exclusion of BC patients with diabetes at study entry, 24.9% of BC survivors self reported diabetes or pre-diabetes (1.99%/year) versus 12.6% in controls (OR 2.3, p= .0017). Conclusion: The metabolic status of long-term BC survivors deteriorated over time and age-adjusted at LTFU were worse with respect to a number of factors compared to the control group. Citation Format: Ana Elisa Lohmann, Marguerite Ennis, Pamela J Goodwin. BMI and metabolic factors in long-term breast cancer survivors: Changes from diagnosis and comparison to non-breast cancer controls [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-09-02.