Central obesity, body mass index, metabolic syndrome and mortality in Mediterranean breast cancer patients

Importance:  Obesity and metabolic disorders have been associated with an increased risk of cancer and with  poorer outcomes in many cohorts of breast cancer (BC) patients, with poor evidence from Mediterranean cohorts. 
Objective: To investigate the prognostic potential of anthropometric variables, namely body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), as well as Metabolic Syndrome (MetS) and its components, in early BC patients living in a Southern Mediterranean region of Italy.
Design: Prospective cohort study enrolling consecutive early BC patients who were treated between January 2009 and December 2013 in Southern Italy. Median follow-up was 11.8 years and ended on June 15th 2022. Physicians who measured the study variables were blinded to patient groupings.
Setting: Multicenter study enrolling consecutive, early BC patients referred to specialized cancer centers.
Participants: A total of 955 early BC patients consecutively treated at the Istituto Nazionale dei Tumori, “G. Pascale” and at the Policlinico University Hospital “Federico II”, Naples, Italy, were enrolled.  All study subjects provided written informed consent to participate. 
Intervention(s) (for clinical trials) and exposure (for observational studies): Anthropometric measurements and indices (BMI, hip circumference and WC) were collected. MetS was defined according to NCEP-ATP III criteria. MetS components were categorized as 0, 1-2 or ≥3. 
Main Outcomes  and Measures: Overall survival and BC-specific survival. 
Results:  Mean age was 55.3 years (±12.5 years); 61% of patients were post-menopausal. At the end of follow-up, 208 (22%) patients had died, 131 (14%) of whom from BC. Obesity (BMI≥30 kg/m2) was found in 29% of enrolled patients (14% in pre- and 38% in post-menopause); 24% of patients met the criteria for a diagnosis of MetS (7% in pre- and 36% in post-menopause), whereas 1-2 MetS criteria were found in 53% of patients
High WC or WHR were associated with a moderately increased risk of all-cause mortality (WC ≥ 88 cm, HR=1.39, 95%CI: 1.00-1.94; WHR > 0.85, HR=1.62, 95%CI: 1.12-2.37). Furthermore, an increased risk of all-cause mortality was observed with the presence of MetS (HR=1.61, 95%CI: 1.12-2.32). An increased BC-specific mortality risk was found in obese patients (BMI≥30 kg/m2, HR=1.72, 95%CI: 1.06-2.78) and in those with WC ≥88 (HR=1.71, 95%CI: 1.12-2.61). High WHR was also associated with increased risk of BC-specific mortality, both when evaluated as a categorical variable (WHR>0.85, HR=1.80, 95%CI: 1.13-2.86) and as a continuous variable (for each 0.1-U increase in WHR, HR=1.33, 95%CI: 1.08-1.63). The presence of MetS was associated with an 81% increased risk of BC-specific mortality (HR=1.81, 95%CI: 1.51-2.85). 
These associations varied according to menopausal status. In particular, in pre-menopausal patients higher BMI was associated with an increased risk of both all-cause and BC-specific mortality (HR=1.43 and HR=1.58, respectively). In post-menopausal women an increased risk of all-cause mortality was found only in the presence of ≥3 MetS components (HR=2.77, 95%CI: 1.09-7.06). The associations among anthropometric variables and all-cause and BC-specific mortality also varied according to BC subtype. Triple negative BC was the only disease subtype that wasn’t independently associated with BMI, WC, WHR or MetS or all-cause and BC-specific mortality.
Conclusions and Relevance: Central obesity and metabolic disorders result in a highly increased risk of BC death. The magnitude of this effect suggests that obesity may nullify the benefit of effective BC therapies. Active lifestyle interventions to maintain optimal body weight and to prevent MetS should be recommended for several expected beneficial effects, including a potential reduction in BC-specific mortality.