Background: Approximately one-half of HER2−positive breast cancer patients will not respond to first-line trastuzumab-containing therapy. Since trastuzumab is now used in the HER2−positive adjuvant breast cancer setting, trastuzumab resistance will continue to be a vexing clinical problem, and better predictive and prognostic biomarkers are urgently needed.
One potential biomarker is serum ferritin. Although serum ferritin has been used as an indicator of total body iron, a specific functional role has not been proposed thus far other than perhaps recycling iron for erythropoiesis. Increased serum ferritin levels have been reported in breast cancer patients. However, the prevailing paradigm on ferritin at the time of these observations did not encourage speculation on its role or significance and was dismissed as a non-specific parameter for cellular damage. There are now multiple lines of evidence that have challenged this traditional paradigm and suggested ferritin to be a multi-functional factor involved in key cellular and systemic processes including immune regulation, angiogenesis, and iron delivery.
Methods: Pretreatment serum ferritin was measured using an ELISA assay in 66 metastatic breast cancer patients before starting first-line trastuzumab-containing therapy. Serum ferritin was determined using an ELISA from Assaypro, St. Charles, MO. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method and Cox modeling, with separate analyses as continuous serum ferritin, or as dichotomous categorical groups using the median pretreatment serum ferritin level as a cut off point. To interrogate a functional impact of elevated serum ferritin, we used a cell culture model.
Results: When analyzed as dichotomous categorical groups using the median pretreatment serum ferritin level as a cut off point, the elevated serum ferritin patient cohort had a significantly reduced OS (P<0.0001, median OS 12.73 vs. 69.57 months) and PFS (P=0.004, 8.30 vs. 23.90 months). In the cell culture model, ferritin bound to breast cancer cells promoted proliferation and activated AKT signaling. These novel observations suggest that the iron storage protein ferritin has a signaling role in tumor biology. Since the elevation in serum ferritin is unlikely a consequence of a change in total body iron, we also examined several possible sources for this elevation. Macrophages, but not breast cancer cells, were capable of ferritin secretion.
Conclusions: Elevated serum ferritin predicts reduced PFS and overall survival in metastatic breast cancer patients treated with first-line trastuzumab-containing therapy. The ability of ferritin to activate AKT signaling could underlie the trastuzumab resistance in patients. Therefore, serum ferritin may not only have predictive value as a clinical tool but also has direct functional significance in the treatment response, progression and survival of breast cancer patients.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-14-11.