The inflammatory cytokine interleukin 6 may be a biomarker for distant recurrence of breast cancer among patients treated for stage II-III HER2-negative disease, investigators have found.
In a case-control study of 498 women with breast cancer treated with surgery and adjuvant chemotherapy, as well as endocrine therapy for women with estrogen receptor (ER)–positive tumors, those with higher serum levels of IL-6 at diagnosis had a significantly greater risk for disease recurrence than women with lower levels of the cytokine, Joseph A. Sparano, MD, from the Albert Einstein College of Medicine and Montefiore Medical Center, New York, and colleagues reported.
“This analysis provides level 1B evidence indicating that higher levels of the cytokine IL-6 at diagnosis are associated with a significantly higher distant recurrence risk in high-risk stage II-III breast cancer despite optimal adjuvant systemic therapy,” they wrote in a study presented in a poster discussion session at the American Society of Clinical Oncology Annual Meeting.(Abstract 520)
In an interview, Dr. Sparano said that their findings first need to be validated in a larger study.
“When validated, I think the other key issue is to try to understand what the best cut point for identifying high risk is, “ he said.
If further studies confirm that higher IL-6 levels are prognostic for worse outcomes, it might be possible to use levels of the cytokine as a biomarker to predict for therapies targeting the IL-6/Janus kinase/STAT3 pathway.
“There are trials ongoing testing IL-6 antibodies in combination chemotherapy, and this could be a rational biomarker to identify which patients would be more likely to benefit from that approach,” he said.
Systemic inflammation
Systemic inflammation is suspected as a contributing factor to cancer progression and disease recurrence, Dr. Sparano and colleagues noted.
To test their hypothesis that inflammatory cytokines and/or chemokines could be associated with distant recurrence, they conducted a case-control study with 249 matched pairs of patients enrolled in a phase 3 trial of adjuvant chemotherapy for lymph-node positive and high-risk lymph-node negative breast cancer (NCT00433511).
The patients all had surgery and adjuvant chemotherapy with doxorubicin, cyclophosphamide, and paclitaxel with or without bevacizumab, and endocrine therapy for patients whose tumors were ER positive.
They used propensity score matching to pair each patient with distant recurrence to one without, with covariates including post versus premenopausal or perimenopausal status, estrogen and/or progesterone receptor positivity, tumor size (less than 2 cm, greater than 2-5 cm, or greater than 5 cm) nodal status, and grade.
The only biomarker that met the prespecified boundary for statistical significance (P < .0014) was IL-6, with a hazard ratio for distant recurrence of 1.37 (P = .0006).
The median and mean values for IL-6 were 0.95 and 7.5 pg/mL, respectively
Other substances associated with distant recurrence (with a two-sided P value < .05) were macrophage-derived chemokine/CCL22 (HR, 1.90; P = .0098), IL-17A, a T-helper cell inflammatory cytokine (HR, 1.36; P = .0052), and the cytokine vascular endothelial growth factor A (VEGF-A, HR, 1.13; P = 0.037).
There was no statistical interaction between VEGF-A levels and the benefit of bevacizumab.