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Obesity and metabolic syndrome are associated with short-term endocrine therapy resistance in early ER + breast cancer

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Abstract

Purpose

Increased body mass index (BMI) and metabolic syndrome (MS) are associated with increased breast cancer recurrence risk. Whether this is due to intrinsic tumor biology or modifiable factors of the obese state remains incompletely understood.

Methods

Oncotype DX Recurrence Scores of 751 patients were stratified by BMI to assess association with tumor-intrinsic recurrence risk. Cellular proliferation by Ki67 after 10–21 days of presurgical letrozole treatment was used to stratify endocrine therapy response (sensitive—ln(Ki67) < 1; intermediate—ln(Ki67)1–2; resistant—ln(Ki67) >  = 2). BMI at the time of surgery and MS variables were collected retrospectively for 143 patients to analyze association between therapy response and BMI/MS. Additionally, PI3K pathway signaling was evaluated by immunohistochemistry of phosphorylated Akt and S6.

Results

There was no significant association between BMI and recurrence score (p = 0.99), and risk score distribution was similar across BMI groups. However, BMI was associated with short-term endocrine therapy resistance, with a significant enrichment of intermediate and resistant tumors in patients with obesity (55%, p = 0.0392). Similarly, the relative risk of an endocrine therapy-resistant tumor was 1.4-fold greater for patients with MS (p = 0.0197). In evaluating PI3K pathway mediators, we found patients with 3 or more MS criteria had more tumors with pAkt scores above the median (p = 0.0436). There were no significant differences in S6 activation.

Conclusion

Our findings suggest the association between obesity/metabolic syndrome and breast cancer recurrence is better reflected by response to treatment than tumor-intrinsic properties, suggesting interventions to reverse obesity and/or MS may improve outcomes for breast cancer recurrence.

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Data availability

The datasets generated during and/or analyzed during the current study are not publicly available due to patient confidentiality but are available from the corresponding author on reasonable request.

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Funding

This work was partially supported by National Institutes of Health grants NIGMS T32GM007347 (R.B.) and NCI SPORE P50CA098131-19 (V.S., M.E.S., P.G.-E., and B.N.R.).

Author information

Author notes

  1. Carlos L. Arteaga

    Present address: UTSW Harold C. Simmons Comprehensive Cancer Center, Dallas, TX, USA

  2. Yvonne A. Berko

    Present address: Currently Piedmont Newnan Hospital, Newnan, Georgia

Authors and Affiliations

  1. Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville, TN, USA

    Riley Bergman, Violeta Sanchez, Melinda E. Sanders, Paula I. Gonzalez-Ericsson, Carlos L. Arteaga & Brent N. Rexer

  2. Meharry Medical College, Nashville, TN, USA

    Yvonne A. Berko

  3. Division of Hematology/Oncology, Vanderbilt University Medical Center, 2220 Pierce Ave, Nashville, TN 777 PRB 37232-6307, USA

    Brent N. Rexer

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Contributions

BNR: designed and initiated the retrospective study; CLA: designed and initiated the original clinical trial for Cohort 2. RB, YB, and BNR: clinical data collection and analysis were performed. VS, MES and PGE: Pathologic and molecular data collection and analysis were performed. BNR and RB: wrote the initial draft of the manuscript. All authors commented on previous versions of the manuscript and read and approved the final manuscript.

Corresponding author

Correspondence to Brent N. Rexer.

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The authors have no relevant financial or non-financial interests to disclose.

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This study was approved by the Vanderbilt University Medical Center Institution Review Board (IRB #191178).

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Bergman, R., Berko, Y.A., Sanchez, V. et al. Obesity and metabolic syndrome are associated with short-term endocrine therapy resistance in early ER + breast cancer. Breast Cancer Res Treat 197, 307–317 (2023). https://doi.org/10.1007/s10549-022-06794-y

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  • DOI: https://doi.org/10.1007/s10549-022-06794-y

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