Randomized trial of weight loss in primary breast cancer: Impact on body composition, circulating biomarkers and tumor characteristics

Wendy Demark-Wahnefried, Laura Q Rogers, Justin T Gibson, Shuko Harada, Andrew D Frugé, Robert A Oster, William E Grizzle, Lyse A Norian, Eddy S Yang, Deborah Della Manna, Lee W Jones, Maria Azrad, Helen Krontiras, Wendy Demark-Wahnefried, Laura Q Rogers, Justin T Gibson, Shuko Harada, Andrew D Frugé, Robert A Oster, William E Grizzle, Lyse A Norian, Eddy S Yang, Deborah Della Manna, Lee W Jones, Maria Azrad, Helen Krontiras

Abstract

Obesity adversely impacts overall and cancer-specific survival among breast cancer patients. Preclinical studies demonstrate negative energy balance inhibits cancer progression; however, feasibility and effects in patients are unknown. A two-arm, single-blinded, randomized controlled weight-loss trial was undertaken presurgery among 32 overweight/obese, Stage 0-II breast cancer patients. The attention control arm (AC) received basic nutritional counseling and upper-body progressive resistance training whereas the weight loss intervention (WLI) arm received identical guidance, plus counseling on caloric restriction and aerobic exercise to promote 0.68-0.92 kg/week weight loss. Anthropometrics, body composition, blood and survey data were collected at baseline and presurgery ∼30 days later. Tumor markers (e.g., Ki67) and gene expression were assessed on biopsy and surgical specimens; sera were analyzed for cytokines, growth and metabolic factors. Significant WLI vs. AC differences were seen in baseline-to-follow-up changes in weight (-3.62 vs. -0.52 kg), %body fat (-1.3 vs. 0%), moderate-to-vigorous physical activity (+224 vs. +115 min/week), caloric density (-0.3 vs. 0 kcal/g), serum leptin (-12.3 vs. -4.0 ng/dl) and upregulation of tumor PI3Kinase signaling and cell cycle-apoptosis related genes (CC-ARG; all p-values <0.05). Cytolytic CD56dim NK cell expression was positively associated with weight loss; CC-ARG increased with physical activity. Increased tumor (nuclear) TNFα and IL-1β, CX3CL1 and CXCL1 gene expression was observed in the WLI. Tumor Ki67 did not differ between arms. Feasibility benchmarks included 80% accrual, 100% retention, no adverse effects and excellent adherence. Short-term weight loss interventions are feasible; however, mixed effects on tumor biology suggest unclear benefit to presurgical caloric restriction, but possible benefits of physical activity.

Keywords: Ki67; breast cancer; clinical trial; diet; exercise.

© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

Figures

Figure 1
Figure 1
Consolidated Standards of Reporting Trials (CONSORT) diagram.
Figure 2
Figure 2
Effects of WLI, weight loss and physical activity on differentially expressed (DE) genes and associated pathways, biological processes and cell types in breast tumor tissues. (a) DE gene‐associated pathways reported from nanoString‐designated gene sets for WLI (n = 12) and AC (n = 12) participants at time of surgery vs. preintervention biopsy. (b) Gene Ontology (GO) Enrichment Analysis and associated GO biological processes of 16 upregulated DE genes in tumor tissue of WLI participants at time of surgery vs. preintervention biopsy. Association of (c) degree of weight loss or (d) accelerometer‐measured physical activity (PA) with nanoString‐identified cell type scores and pathway scores.
Figure 3
Figure 3
DE genes in WLI vs. AC tumor specimens at time of surgery. Heatmaps depicting DE genes identified from nanoString (a) PanCancer Pathways and (b) PanCancer Immune Profiling panels.

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