Prognostic impact of body mass index (BMI) in HER2+ breast cancer treated with anti-HER2 therapies: from preclinical rationale to clinical implications

Abstract

Human Epidermal growth factor Receptor 2 (HER2) overexpression or HER2 gene amplification defines a subset of breast cancers (BCs) characterized by higher biological and clinical aggressiveness. The introduction of anti-HER2 drugs has remarkably improved clinical outcomes in patients with both early-stage and advanced HER2+ BC. However, some HER2+ BC patients still have unfavorable outcomes despite optimal anti-HER2 therapies. Retrospective clinical analyses indicate that overweight and obesity can negatively affect the prognosis of patients with early-stage HER2+ BC. This association could be mediated by the interplay between overweight/obesity, alterations in systemic glucose and lipid metabolism, increased systemic inflammatory status, and the stimulation of proliferation pathways resulting in the stimulation of HER2+ BC cell growth and resistance to anti-HER2 therapies. By contrast, in the context of advanced disease, a few high-quality studies, which were included in a meta-analysis, showed an association between high body mass index (BMI) and better clinical outcomes, possibly reflecting the negative prognostic role of malnourishment and cachexia in this setting. Of note, overweight and obesity are modifiable factors. Therefore, uncovering their prognostic role in patients with early-stage or advanced HER2+ BC could have clinical relevance in terms of defining subsets of patients requiring more or less aggressive pharmacological treatments, as well as of designing clinical trials to investigate the therapeutic impact of lifestyle interventions aimed at modifying body weight and composition. In this review, we summarize and discuss the available preclinical evidence supporting the role of adiposity in modulating HER2+ BC aggressiveness and resistance to therapies, as well as clinical studies reporting on the prognostic role of BMI in patients with early-stage or advanced HER2+ BC.

Keywords: BMI; HER2+ BC; anti-HER2 drugs; clinical outcomes; molecular mechanisms.

Figure 1.

Biological mechanisms at the basis of the link between patient adiposity and clinical outcomes in HER2+ BC. Top, left: Increased IGF-1, IGF-2, and insulin levels typical of overweight/obese people could contribute to an overactivation of IR and IGF-1R pathways. These axes in turn lead to the stimulation of PI3K/AKT and MAPK pathways. IGF-1R activation can also stimulate the phosphorylation of HER2 in an Src-dependent manner, and it is able to reverse the p27 Kip1-mediated cell cycle arrest induced by trastuzumab. Finally, IGF-1R induces the expression of FoxM1. Top, right: Leptin, through OB-R, induces the activation of JAK/STAT, MAPK, and PI3K axes; it also can stimulate the expression of cyclin D1, CDK2, and cMyc, as well as of VEGF and VEGF-R2. OB-R can increase HER2 protein levels via STAT3; finally, it can transactivate ERα. Left: Overweight and obesity can affect the pharmacokinetics of anti-HER2 drugs, with an inverse proportional relationship between patient BMI and trastuzumab plasma concentration. Right: In overweight/obese HR+/HER2+ BC patients, an increased activation of the aromatase enzyme in the adipose tissue can lead to increased estradiol concentrations, thus antagonizing the effect of hormonal treatments. Bottom: Given the relevance of plasmatic lipid uptake in modulating HER2+ BC cell growth, proliferation, and resistance to treatments, increased circulating lipid concentrations typical of overweight/obese people could affect HER2+ BC patient outcome. ACC1, acetyl-CoA carboxylase; AMPK, 5′ adenosine monophosphate-activated protein kinase; ATGs, autophagy-related; BMI, body mass index; CycD1, cyclin D1; ERα, estrogen receptor alpha; ERK, extracellular signal-regulated kinase; FA, fatty acid; FASN, fatty acid synthase; 4EBP1, Eukaryotic Translation Initiation Factor 4E-Binding Protein 1; FoxM1, Forkhead Box M1; Grb2, growth factor receptor-bound protein 2; IGF-1R, Insulin-like Growth Factor 1 receptor; IGF-2R, Insulin-like Growth Factor 2 receptor; IR, insulin receptor; IRS1, insulin receptor substrate 1; LKB1, liver kinase B1; LPL, lipoprotein lipase; MEK, mitogen-activated protein kinase kinase; mTORC1, mammalian Target of Rapamycin Complex 1; OB-R, leptin receptor; PDK1, phosphoinositide-dependent kinase-1; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; PTEN, phosphatase and tensin homolog; RAF, rapidly accelerated fibrosarcoma; RAS, rat sarcoma virus; SKP2, S-Phase Kinase Associated Protein 2; SOS, Ras/Rac Guanine Nucleotide Exchange Factor 1; S6K, S6 kinase; TG, triglyceride; TSC1, Tuberous Sclerosis 1; TSC2, Tuberous Sclerosis 2; ULK1, Unc-51 Like Autophagy Activating Kinase 1; VEGF, vascular endothelial growth factor.