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Background: Hepcidin is thought to be the central regulator of iron metabolism. Iron deficiency is associated with low hepcidin concentrations, and anemia in patients with cancer is associated with high concentrations of hepcidin. Study objectives: Our main objective was to assess the potential role of hepcidin for predicting response to epoetin therapy in anemic cancer patients. We also aimed to identify a cutoff value for hepcidin as a potential predictive marker for response to epoetin therapy. Methods: Using data from 525 anemic cancer patients enrolled in 5 studies, we assessed serum hepcidin concentrations in 408 of these patients at baseline and analyzed pooled data from the 408 patients. The analysis population was separated into 2 categories using a threshold hepcidin concentration of 13 nmol/L: low hepcidin (<13 nmol/L) and high hepcidin (≥13 nmol/L). Results: A significantly higher percentage of responders (defined as hemoglobin increase ≥10 g/L or ≥20 g/L from baseline) was observed in the low hepcidin group compared with the high hepcidin group (P = 0.04 for ≥10 g/L increase and P = 0.009 for ≥20 g/L from baseline). There was also a statistically significant difference between the 2 groups for hematopoietic response (hemoglobin rise at least once ≥20 g/L from baseline or at least once ≥120 g/L) to epoetin therapy (P = 0.0004). Conclusions: The results of this analysis suggest a potential role of hepcidin serum concentrations in predicting the response to epoetin therapy.

This multicenter single-arm phase II study evaluated the addition of pazopanib to concurrent weekly paclitaxel following doxorubicin and cyclophosphamide as neoadjuvant therapy in human epidermal growth factor receptor (HER2)-negative locally advanced breast cancer (LABC). Patients with HER2-negative stage III breast cancer were treated with doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) for four cycles every 3 weeks followed by weekly paclitaxel 80 mg/m(2) on days 1, 8, and 15 every 28 days for four cycles concurrently with pazopanib 800 mg orally daily prior to surgery. Post-operatively, pazopanib was given daily for 6 months. The primary endpoint was pathologic complete response (pCR) in the breast and lymph nodes. Between July 2009 and March 2011, 101 patients with stage IIIA-C HER2-negative breast cancer were enrolled. The pCR rate in evaluable patients who initiated paclitaxel and pazopanib was 17 % (16/93). The pCR rate was 9 % (6/67) in hormone receptor-positive tumors and 38 % (10/26) in triple-negative tumors. Pre-operative pazopanib was completed in only 39 % of patients. The most frequent grade 3 and 4 adverse events during paclitaxel and pazopanib were neutropenia (27 %), diarrhea (5 %), ALT and AST elevations (each 5 %), and hypertension (5 %). Although the pCR rate of paclitaxel and pazopanib following AC chemotherapy given as neoadjuvant therapy in women with LABC met the pre-specified criteria for activity, there was substantial toxicity, which led to a high discontinuation rate of pazopanib. The combination does not appear to warrant further evaluation in the neoadjuvant setting for breast cancer.

Background: Clinical validity of CTCs (CellSearch®) in metastatic breast cancer (MBC) patients has previously been assessed in studies with limited statistical power. We aimed to pool all European studies to obtain high-level evidence on the prognostic value of CTCs, to investigate their effects across different clinico-pathological characteristics and therapies and to further validate the MD Anderson/Institut Curie/Fox Chase CTC-based prognostic nomogram established in first-line treated MBC patients (Giordano et al, Clin Cancer Res 2013). Material and methods: Methods were predefined in a written protocol. In December 2012, we searched for eligible studies that accrued patients in 2003-2012. We contacted all European laboratories using CellSearch®. We used likelihood ratio tests (LR) in Cox regression models stratified by study to assess the independent prognostic value of CTC when added to a clinicopathological (CP) model for progression-free (PFS) and overall survival (OS). Landmark analyses were used to assess the prognostic effect of early changes in CTC. The CTC-based nomogram (http://cancernomograms.com/CTCOnline.html) score was retrieved for every patient; we calculated C-indices, drew calibration plots and Kaplan-Meier curves according to quintiles of the nomogram score. Results: We collected individual data of 1944 MBC patients, from 20 different studies (some unpublished), from 17 centers in 7 European countries. We observed 1507 PFS events and 929 deaths. Baseline CTC count was significantly associated with several patient characteristics, such as performance status (PS, p<10-4), synchronous metastasis (p<10- 2) tumor subtype (p<10-4), liver & bone metastases (p<10-4), CEA & CA15-3 levels (p<10-4). The CP model for OS included PS, MBC subtypes, number of previous lines of treatment, patient's age, metastasis-free interval, metastatic sites (p<0.01 for all). In a multivariate analysis containing the CP model parameters and CTC count at baseline, elevated CTC count (≥5) was a significant independent predictor of OS (n = 1444, HR = 2.7, 95%CI [2.2-3.2], LR p<10-4). Baseline serum markers added either no or marginal effect to the CP plus baseline CTC model for OS. In contrast, early changes in CTC status at week 3-5 significantly added prognostic information for OS to the model with CP factors and baseline CTC+ (n = 569, HR = 1.8 [2.2-3.2], LR p<0.001). In the population of interest (MBC treated by first line chemotherapy, n = 402 patients, 176 deaths), the CTC-based nomogram exhibited a good C-index for OS (0.69), was well calibrated and showed clear separation of the survival curves. Additional results, including subgroup analyses by tumor subtype and treatments will be presented at the meeting. Conclusions: This pooled analysis is the largest study ever reported on CTC in MBC, with a previously unreached statistical power. It provides a clear level-of-evidence 1 on the independent prognostic value of CTCs before and during treatment in MBC. Also, the CTC-based prognostic nomogram is independently validated. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD6-5.

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