**Background:** Breast cancer is the most common cancer and leading cause of cancer death in women globally, with 2.3 million incident cases and 0.7 million deaths estimated in 2020. As of end of 2020, there were 7.8 million women worldwide who had survived at least 5 years after diagnosis. Higher body fatness and adult weight gain are established risk factors for postmenopausal breast cancer, but the impact on breast cancer outcomes after diagnosis has been less clear. Previous meta-analyses from the WCRF/AICR Third Export Report (published up to June 30, 2012) showed increased risks of all-cause and breast cancer-specific mortality with higher postdiagnosis BMI, but the evidence was judged as limited-suggestive due to concerns about residual confounding and reverse causation. This updated systematic review and meta-analysis was conducted to summarize evidence published through October 31, 2021.
**Methods:** PubMed and Embase were searched for relevant publications through October 31, 2021. Inclusion criteria were: (1) RCTs, longitudinal observational studies, or pooled analyses; (2) at least 100 women diagnosed with first primary breast cancer during adulthood; (3) reported results on postdiagnosis BMI, waist circumference, waist-hip-ratio, or changes in weight/BMI in relation to specified outcomes. Summary relative risk (RR) estimates and 95% confidence intervals (CIs) were calculated using inverse variance random-effects models. Linear dose-response meta-analyses were conducted when at least three studies were identified. Nonlinear dose-response analyses used restricted cubic spline regression with three knots. An independent Expert Panel graded the evidence using pre-defined criteria.
**Key Results:** Overall, 376 publications were identified, with 220 publications (226 studies) included, comprising over 456,000 women diagnosed with breast cancer, of whom over 36,000 died of any causes, approximately 21,000 died of breast cancer, and approximately 30,000 experienced an additional breast cancer event. The meta-analyses included 101 publications reporting postdiagnosis BMI, waist circumference, waist-to-hip ratio, and pre- to postdiagnosis weight gain or loss.
Higher postdiagnosis BMI was associated with higher risks of all-cause mortality (summary RR per 5 kg/m²: 1.07, 95% CI: 1.05-1.10; 64 studies, 32,507 deaths; I²=56%), breast cancer-specific mortality (1.10, 95% CI: 1.06-1.14; 39 studies, 14,106 deaths; I²=60%), breast cancer recurrence (1.05, 95% CI: 1.03-1.08; 63 studies, 29,749 events; I²=54%), and second primary breast cancer (1.14, 95% CI: 1.04-1.26; 11 studies, 5,248 events; I²=66%). There was suggestion of positive associations between BMI and nonbreast cancer-related mortality (1.06, 95% CI: 0.94-1.19; I²=78%) and cardiovascular mortality (1.16, 95% CI: 0.96-1.41; I²=0%).
Nonlinear dose-response analysis detected a J-shaped relationship with all-cause mortality (P nonlinearity <.001), with increased risks for BMI below 18 kg/m² and above 32 kg/m², and the most favorable survival in the upper normal to low overweight range (24-26 kg/m²). Increased risk of breast cancer-specific mortality was evident for BMI above 29 kg/m² (P nonlinearity=.02).
Higher waist circumference and waist-to-hip ratio were associated with higher risks of all-cause mortality (RR per 10 cm: 1.18, 95% CI: 1.07-1.31; RR per 0.1 unit: 1.30, 95% CI: 1.20-1.40) and breast cancer-specific mortality (RR per 10 cm: 1.12, 95% CI: 1.03-1.22; RR per 0.1 unit: 1.21, 95% CI: 1.08-1.35).
For weight change, one RCT of 338 postmenopausal women suggested improved survival with lifestyle intervention (HR 0.71, 95% CI: 0.41-1.24 for disease-free survival; 0.86, 0.35-2.14 for overall survival), but weight loss was not sustainable. Observational studies showed substantial heterogeneity, with suggestion that weight loss (unknown causes) was associated with higher all-cause mortality.
**Clinical Implications:** The evidence was graded as strong (subgrade: probable) for body fatness and all-cause mortality, breast cancer-specific mortality, and second primary breast cancer. The evidence for breast cancer recurrence was graded as limited-suggestive due to inconsistent outcome definitions. The evidence for weight or BMI change was graded as limited-no conclusion due to sparse and inconsistent data. The review supports advising women who have completed primary treatment for breast cancer to follow WCRF/AICR Cancer Prevention Recommendations to eat a healthy diet, be physically active, and maintain a healthy weight. However, to reach a convincing evidence grade, more definitive evidence from RCTs on body composition, weight control, or weight loss is needed. The authors note that cardiovascular deaths are the most common cause of nonbreast cancer deaths in breast cancer patients, and more research on cardiovascular mortality is warranted.