Abstract P3-08-08: Prognostic associations of plasma hepcidin in early breast cancer (BC)
Authors: Jerzak KJ , Lohmann AE , Ennis M , Nemeth E , Ganz T , Goodwin PJ 
Published: February 2018

Background: Intra-tumor RNA expression of hepcidin has been linked to adverse metastasis-free survival in women with early BC, but the prognostic implications of this inflammatory marker and iron-regulating peptide are unknown.

Methods: Using an ELISA assay, we measured plasma hepcidin in the banked blood of 518 women who were recruited from 1989-1996 for a prospective cohort study regarding diet and lifestyle factors in BC. Blood had been obtained 4-12 weeks post-operatively and prior to treatment with radiation, chemotherapy or hormonal therapy. Women ages 18 to 75 with T1-3, N0-1, M0 BC who underwent surgery and axillary dissection were included; those with metabolic disorders were excluded. Tumor size, grade and ER/PR expression were abstracted from pathology reports; HER2 status was unknown. Median follow-up was 12.1 years (range, 0.2 to 17 years).

Univariable Cox regression models were used to determine the association between hepcidin and i) time to distant BC recurrence (primary outcome), and ii) time to death due to any cause. Multivariable Cox proportional hazards models were adjusted for age (continuous), T stage (T2, T3, Tx vs T1), tumor grade (3 vs 2 or 1), N stage (node positive vs negative), ER/PR expression (both ER and PR negative vs either positive) a-priori. Associations between hepcidin and CRP, IL6, insulin, cholesterol, glucose, vitamin D, total iron, transferrin, and soluble transferrin receptor; sTfR were explored (Pearson's coefficients).

Results: Hepcidin ranged from 4.70-190.70 ng/L (median 16.25; IQR 16.40 ng/L). To ensure normal distribution, a transformed [-1/sqrt (x)] hepcidin variable was used for prognostic analyses. Average age was 50.3±9.7 years. 16% were obese [body mass index (BMI) &gt;30kg/m2], 30% (n=156) were node positive, 35% (n=181) had grade 3 tumors and 71% (n=370) had ER and/or PR positive tumors. 77% underwent a lumpectomy, 73% (n=380) received adjuvant radiotherapy and 39% (n=203) received adjuvant chemotherapy.

Plasma hepcidin was not univariably associated with either time to distant BC recurrence (HR for 75th percentile versus 25th 1.20; 95%CI 0.79-1.32) or time to death due to any cause (HR 1.23; 95%CI 0.95-1.59) in the overall cohort; multivariable results were similar. In pre-planned analyses, the prognostic association of hepcidin differed by BMI (≤30 vs &gt;30 kg/m2; interaction p-values &lt;0.05): among obese women, higher hepcidin was significantly associated with a shorter time to distant BC recurrence in both univariable (HR 1.81; 95%CI 1.06–3.10) and multivariable (HR 1.84; 95%CI 1.04–3.25) models. Higher hepcidin was associated with shorter time to death due to any cause in a univariable model (HR 1.91; 95%CI 1.13–3.22) but not in a multivariable analysis. There was a moderate association between hepcidin and total iron (r=0.35), transferrin (r=0.43) and sTfR (r=-0.39); associations with IL6, CRP and metabolic factors were very weak (r&lt;0.2).

Conclusion: Higher plasma hepcidin was independently associated with a shorter time to distant BC recurrence in obese women but not in the overall cohort. Further investigation of hepcidin and mechanisms linking it to adverse BC outcomes is warranted.

Citation Format: Jerzak KJ, Lohmann AE, Ennis M, Nemeth E, Ganz T, Goodwin PJ. Prognostic associations of plasma hepcidin in early breast cancer (BC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-08-08.