Effects of systemic inflammation on relapse in early breast cancer

Nicholas P Mcandrew,Ian A Blair,Tapan Ganguly,Patricia Y Tsao,Lisa Bottalico,Clementina Mesaros,Sarah J Song,Jennifer M Rosado,Angela Demichele,Phyllis A Gimotty,Jun J Mao

doi:10.1038/s41523-020-00212-6

Abstract

Chronic inflammation has been a proposed mechanism of resistance to aromatase inhibitors in breast cancer. Stratifying by HER2 status, a matched case-control study from the Wellness After Breast Cancer-II cohort was performed to assess whether or not elevated serum inflammatory biomarkers (C-Reactive protein [CRP], interleukin-6 [IL-6], and serum amyloid A [SAA]) and/or the presence of a high-risk IL-6 promoter genotype were associated with recurrence of hormone receptor positive (HR+) early breast cancer. Estrogen levels were also measured and correlated with biomarkers and disease outcomes. CRP and SAA were significantly associated with an increased risk of recurrence in the HR+/HER2− group, but not the HR+/HER2+ group. Mean serum estrogen levels were non-significantly elevated in patients who relapsed vs. non-relapsed patients. Surprisingly, high-risk IL-6 promoter polymorphisms were strongly associated with HER2+ breast cancer relapse, which has potential therapeutic implications, as elevated intracellular IL-6 has been associated with trastuzumab resistance in pre-clinical models.

Highlights

Estrogen receptor positive (ER+) breast cancer represents approximately 60–80% of all breast cancer diagnoses[1]
HER2− cohort Patients for this nested case-control study were identified from among a total of 1287 patients enrolled to the parent cohort, the Wellness After Breast Cancer-II (WABC-II) cohort study
To examine early treatment failure we identified a total of 197 unique cases consisting of those patients with stage I–III ER+ breast cancer who relapsed on or after adjuvant Aromatase inhibitors (AIs) and matched controls who remained free of recurrence during or after AI therapy for this

Summary

Introduction

Estrogen receptor positive (ER+) breast cancer represents approximately 60–80% of all breast cancer diagnoses[1]. Aromatase inhibitors (AIs) have revolutionized treatment for this disease by blocking the peripheral conversion of androgens to estrogen, primarily in adipose tissue[2] thereby reducing recurrence and improving survival in the adjuvant setting. These benefits extend to both post-menopausal and high-risk premenopausal women (when combined with ovarian suppression). While there are multiple inflammatory pathways and molecules that have been implicated in ER+ breast cancer recurrence[5,6,7], the inflammatory cytokine interleukin-6 (IL-6) and its associated pathway has been shown to be associated with poor outcomes in ER+ breast cancer[8]. Functional polymorphisms in the IL-6 promoter that result in increased transcription of IL-6 are significantly associated with worse prognosis and decreased disease free survival (DFS) in high-risk breast cancer patients[9]

Methods

Results

Conclusion