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Background: Obesity is a major negative determinant of breast cancer outcome. However, there are contrasting data on the differential impact of obesity on specific breast cancer subtypes. In particular, very little is known on human epidermal growth factor receptor 2-positive (HER2+) tumours. Patients and methods: We assessed the prognostic role of increased body mass index (BMI) on a consecutive series of non-metastatic HER2+ patients treated at our institution before the introduction of adjuvant Trastuzumab. We separately analysed oestrogen receptor-positive (ER+) and -negative (ER-) HER2+ cases. Results: In ER-/HER2+ tumours we observed a significantly worse overall survival (Hazard ratio (HR) 1.79, p-value 0.041) and cumulative incidence of distant metastases (HR 2.03, p-value 0.019) in obese (BMI > 30) versus normal/underweight (BMI < 25) patients. Local relapses appeared to be non-significantly reduced in obese patients, masking the overall effect on disease-free survival. Outcome in ER+ tumours, instead, was not significantly different between BMI groups. Conclusions: Obesity significantly correlates with worse overall survival and cumulative incidence of distant metastases in ER-/HER2 positive breast cancer. Differences in the biology of breast tumours may determine individual susceptibility to obesity. The biology of the underlying tumour should be taken into account in the design of dietary intervention trials in breast cancer. © 2013 Elsevier Ltd. All rights reserved.

We (Breccia et al, Blood 2012) recently reported that risk and prognosis of Acute Promyelocytic Leukemia (APL) is strongly affected by an elevated body mass index (BMI). In our cohort, overweight/obese patients had a 3-fold higher cumulative incidence of relapse at 5 years (31,6% vs 11.2%, p=0.029) and BMI was found to be an independent prognostic factor at multivariate analysis. As the prevalence of overweight/obesity increases in the Western world, it becomes imperative to understand which molecular mechanisms mediate the interaction between systemic metabolism and APL, and cancer in general. Importantly, it remains to be proven that dietary interventions aimed at weight loss can provide any clinical benefit for cancer patients. Mouse models of leukemia provide a tractable system to address such questions experimentally.

We investigated whether body mass index (BMI) correlates with distinct outcomes in newly diagnosed acute promyelocytic leukemia (APL). The study population included 144 patients with newly diagnosed and genetically confirmed APL consecutively treated at a single institution. All patients received All-trans retinoic acid and idarubicin according to the GIMEMA protocols AIDA-0493 and AIDA-2000. Outcome estimates according to the BMI were carried out together with multivariable analysis for the risk of relapse and differentiation syndrome. Fifty-four (37.5%) were under/normal weight (BMI < 25), whereas 90 (62.5%) patients were overweight/obese (BMI ≥ 25). An increased BMI was associated with older age (P < .0001) and male sex (P = .02). BMI was the most powerful predictor of differentiation syndrome in multivariable analysis (odds ratio = 7.24; 95% CI, 1.50-34; P = .014). After a median follow-up of 6 years, the estimated cumulative incidence of relapse at 5 years was 31.6% (95% CI, 22.7%-43.8%) in overweight/obese and 11.2% (95% CI, 5.3%-23.8%) in underweight/normal weight patients (P = .029). Multivariable analysis showed that BMI was an independent predictor of relapse (hazard ratio = 2.45, 95% CI, 1.00-5.99, in overweight/obese vs under/normal weight patients, P = .049). An increased BMI at diagnosis is associated with a higher risk of developing differentiation syndrome and disease relapse in APL patients treated with AIDA protocols. © 2012 by The American Society of Hematology.

Chemotherapy-free regimens are now a realistic goal in Acute Promyelocytic Leukemia (APL), as demonstrated by recent studies combining All-Trans Retinoic Acid (ATRA) with Arsenic Trioxide and Gemtuzumab Ozogamicin. Combinations of ATRA with kinase inhibitors, which have shown tremendous efficacy in several malignancies, are interesting alternatives but remain poorly characterized in APL. The Insulin-like growth factor 1 (IGF1) pathway is an attractive drug target because of its pervasive involvement in cell proliferation and metabolism of cancer cells. A variety of strategies to target the Insulin/IGF1 axis have been developed, but trials have struggled to demonstrate real efficacy over standard treatments, probably due to our still incomplete understanding of the intricacies of the downstream signalling cascade. Importantly, recent evidence suggests that inhibition of the sole IGF1 receptor may be inadequate because the structurally similar insulin receptor (IR) or IGF1R/IR heterodimeric receptors may be sufficient to support tumour growth. We dissected the IGF1R/IR pathway in the well established APL cell line NB4. IGF1 and insulin, but not the structurally similar IGF1R ligand IGF2, significantly increased NB4 growth in serum-free medium. ATRA treatment resulted in the downregulation, at both transcript and protein level, of several components of the proximal IR/IGF1R pathway: IGF1R (down by 64,9 ±1,7%), IR (down by 82,5 ±4,9%), the transducer proteins insulin receptor substrate 1 (IRS1) (down by 85,7 %) and IRS2 insulin receptor IRS2) by 98,1% (+/− 0,8). However, the downstream cascade remained ligand-responsive: stimulation of serum-starved cells with IGF1 induced a dose-dependent phosphorylation of AKT, FOXO, the mTOR target ribosomal protein S6 and ERK1-2. In addition, baseline levels of phospho-ERK were elevated after ATRA treatment. This suggested that ATRA-treated cells may increase their dependence on IGF1R for their survival. In agreement with this model