Prognostic Impact of Body Mass Index (BMI) in HER2+ Breast Cancer Treated with Anti-HER2 Therapies: from Preclinical Rationale to Clinical Implications

Overview

Journal Ther Adv Med Oncol

Specialty Oncology

Date 2022 Mar 14

PMID 35281350

Authors

Francesca Ligorio

Luca Zambelli

Giovanni Fuca

Riccardo Lobefaro

Marzia Santamaria

Emma Zattarin

Filippo De Braud

Claudio Vernieri

Affiliations

Soon will be listed here.

Abstract

Human Epidermal growth factor Receptor 2 (HER2) overexpression or 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.

Citing Articles

Predicting HER2 Status Associated with Breast Cancer Aggressiveness Using Four Machine Learning Models.

Boulmaiz A, Berredjem H, Cheikchouk K, Boulkrah A, Aouras H, Djedi H Asian Pac J Cancer Prev. 2024; 25(10):3609-3618.

PMID: 39471028 PMC: 11711339. DOI: 10.31557/APJCP.2024.25.10.3609.

Pre-treatment [18F]FDG PET/CT biomarkers for the prediction of antibody-drug conjugates efficacy in metastatic breast cancer.

Seban R, Champion L, De Moura A, Lerebours F, Loirat D, Pierga J Eur J Nucl Med Mol Imaging. 2024; 52(2):708-718.

PMID: 39373900 DOI: 10.1007/s00259-024-06929-x.

Impact of body mass index in therapeutic response for HER2 positive breast cancer treated with neoadjuvant targeted therapy: a multi-center study and meta-analysis.

Chen L, Wu F, Chen X, Chen Y, Deng L, Cai Q NPJ Breast Cancer. 2023; 9(1):46.

PMID: 37258524 PMC: 10232579. DOI: 10.1038/s41523-023-00552-z.

The pan-immune-inflammation value is associated with clinical outcomes in patients with advanced TNBC treated with first-line, platinum-based chemotherapy: an institutional retrospective analysis.

Provenzano L, Lobefaro R, Ligorio F, Zattarin E, Zambelli L, Sposetti C Ther Adv Med Oncol. 2023; 15:17588359231165978.

PMID: 37063779 PMC: 10102956. DOI: 10.1177/17588359231165978.

References

Gallagher E, LeRoith D . The proliferating role of insulin and insulin-like growth factors in cancer. Trends Endocrinol Metab. 2010; 21(10):610-8. PMC: 2949481. DOI: 10.1016/j.tem.2010.06.007. View

Ishikawa M, Kitayama J, Nagawa H . Enhanced expression of leptin and leptin receptor (OB-R) in human breast cancer. Clin Cancer Res. 2004; 10(13):4325-31. DOI: 10.1158/1078-0432.CCR-03-0749. View

Modi S, Saura C, Yamashita T, Park Y, Kim S, Tamura K . Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med. 2019; 382(7):610-621. PMC: 7458671. DOI: 10.1056/NEJMoa1914510. View

Sestak I, Distler W, Forbes J, Dowsett M, Howell A, Cuzick J . Effect of body mass index on recurrences in tamoxifen and anastrozole treated women: an exploratory analysis from the ATAC trial. J Clin Oncol. 2010; 28(21):3411-5. DOI: 10.1200/JCO.2009.27.2021. View

Mazzarella L, Disalvatore D, Bagnardi V, Rotmensz N, Galbiati D, Caputo S . Obesity increases the incidence of distant metastases in oestrogen receptor-negative human epidermal growth factor receptor 2-positive breast cancer patients. Eur J Cancer. 2013; 49(17):3588-97. DOI: 10.1016/j.ejca.2013.07.016. View

Bado A, Levasseur S, Attoub S, Kermorgant S, Laigneau J, Bortoluzzi M . The stomach is a source of leptin. Nature. 1998; 394(6695):790-3. DOI: 10.1038/29547. View

Arpino G, Wiechmann L, Osborne C, Schiff R . Crosstalk between the estrogen receptor and the HER tyrosine kinase receptor family: molecular mechanism and clinical implications for endocrine therapy resistance. Endocr Rev. 2008; 29(2):217-33. PMC: 2528847. DOI: 10.1210/er.2006-0045. View

Nahta R, Yuan L, Zhang B, Kobayashi R, Esteva F . Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. Cancer Res. 2005; 65(23):11118-28. DOI: 10.1158/0008-5472.CAN-04-3841. View

Dufourny B, Alblas J, van Teeffelen H, van Schaik F, van der Burg B, Steenbergh P . Mitogenic signaling of insulin-like growth factor I in MCF-7 human breast cancer cells requires phosphatidylinositol 3-kinase and is independent of mitogen-activated protein kinase. J Biol Chem. 1998; 272(49):31163-71. DOI: 10.1074/jbc.272.49.31163. View

10.

Kim A, Lee Y, Kim K, Lee J, Lee H, Jang S . Adiponectin represses colon cancer cell proliferation via AdipoR1- and -R2-mediated AMPK activation. Mol Endocrinol. 2010; 24(7):1441-52. PMC: 5417469. DOI: 10.1210/me.2009-0498. View

11.

Wu M, Chou Y, Chou W, Hsu G, Chu C, Yu C . Circulating levels of leptin, adiposity and breast cancer risk. Br J Cancer. 2009; 100(4):578-82. PMC: 2653731. DOI: 10.1038/sj.bjc.6604913. View

12.

Papa V, Gliozzo B, Clark G, McGuire W, Moore D, Fujita-Yamaguchi Y . Insulin-like growth factor-I receptors are overexpressed and predict a low risk in human breast cancer. Cancer Res. 1993; 53(16):3736-40. View

13.

Kern P, Di Gregorio G, Lu T, Rassouli N, Ranganathan G . Adiponectin expression from human adipose tissue: relation to obesity, insulin resistance, and tumor necrosis factor-alpha expression. Diabetes. 2003; 52(7):1779-85. DOI: 10.2337/diabetes.52.7.1779. View

14.

Reggiani F, Labanca V, Mancuso P, Rabascio C, Talarico G, Orecchioni S . Adipose Progenitor Cell Secretion of GM-CSF and MMP9 Promotes a Stromal and Immunological Microenvironment That Supports Breast Cancer Progression. Cancer Res. 2017; 77(18):5169-5182. DOI: 10.1158/0008-5472.CAN-17-0914. View

15.

Tsuchiya T, Shimizu H, Horie T, Mori M . Expression of leptin receptor in lung: leptin as a growth factor. Eur J Pharmacol. 1999; 365(2-3):273-9. DOI: 10.1016/s0014-2999(98)00884-x. View

16.

Protani M, Coory M, Martin J . Effect of obesity on survival of women with breast cancer: systematic review and meta-analysis. Breast Cancer Res Treat. 2010; 123(3):627-35. DOI: 10.1007/s10549-010-0990-0. View

17.

Yang H, Zhou B, Hung M, Lee M . Oncogenic signals of HER-2/neu in regulating the stability of the cyclin-dependent kinase inhibitor p27. J Biol Chem. 2000; 275(32):24735-9. DOI: 10.1074/jbc.C000147200. View

18.

Ryan D, Kushner R . The state of obesity and obesity research. JAMA. 2010; 304(16):1835-6. DOI: 10.1001/jama.2010.1531. View

19.

Okumura M, Yamamoto M, Sakuma H, Kojima T, Maruyama T, Jamali M . Leptin and high glucose stimulate cell proliferation in MCF-7 human breast cancer cells: reciprocal involvement of PKC-alpha and PPAR expression. Biochim Biophys Acta. 2002; 1592(2):107-16. DOI: 10.1016/s0167-4889(02)00276-8. View

20.

Martel S, Poletto E, Ferreira A, Lambertini M, Sottotetti F, Bertolini I . Impact of body mass index on the clinical outcomes of patients with HER2-positive metastatic breast cancer. Breast. 2017; 37:142-147. DOI: 10.1016/j.breast.2017.11.004. View