Impact of adding the multikinase inhibitor sorafenib to endocrine therapy in metastatic estrogen receptor-positive breast cancer

Abstract

Background: Targeting growth factor and survival pathways may delay endocrine-resistance in estrogen receptor-positive breast cancer.

Materials & methods: A pilot Phase II study adding sorafenib to endocrine therapy in 11 patients with metastatic estrogen receptor-positive breast cancer was conducted. Primary end point was response by RECIST after 3 months of sorafenib. Secondary end points included safety, time to progression and biomarker modulation. The study closed early owing to slow accrual.

Results: Eight out of 11 patients had progressive disease on study entry and three had stable disease. Of the ten evaluable patients, seven experienced stable disease (70%) and three experienced progressive diseas (30%), with a median time to progression of 6.1 months (8.4 months in the seven patients on tamoxifen). The serum samples demonstrated a significant reduction in VEGF receptor 2 and PDGF receptor-α. Microarray analysis identified 32 suppressed genes, no induced genes and 29 enriched Kyoto Encyclopedia of Genes and Genomes pathways.

Conclusion: The strategy of adding a targeted agent to endocrine therapy upon resistance may be worthwhile testing in larger studies.

Trial registration: ClinicalTrials.gov NCT00525161.

Keywords: PDGF receptor-α; Ras/Raf/MAPK; VEGF receptor 2; angiogenesis; breast cancer; endocrine resistance.

Figures

Figure 1. Clinical trial schema

Patients on ET for at least 3 months with PD or SD and measurable disease received sorafenib 400 mg b.i.d. daily and response was assessed after 3 months. Baseline serum and tumor biopsies, where applicable, were collected on study entry and after 28 days of sorafenib. Patients were followed until disease progression or unacceptable toxicity. b.i.d.: Twice daily; ER: Estrogen receptor; ET: Endocrine therapy; PD: Progressive disease; PDGFR: PDGF receptor; PgR+: Progesterone receptor positive; p.o.: Per os; SD: Stable disease; VEGFR: VEGF receptor.

Figure 2. Kaplan–Meier survival graphs of median time to progression: product-limit survival estimates

(A) All patients in study (n = 11). Median TTP = 6.1 months (95% CI: 2.6–11.3). (B) Patients receiving tamoxifen on entry (n = 7). Median TTP = 8.4 months (95% CI: 2.6–36). TTP: Time to progression.

Figure 3. Comparison of serum biomarkers by ELISA in individual patient paired samples after adding sorafenib to endocrine therapy (day 1 vs 28)

Biomarkers shown are (A) VEGF, (B) human soluble VEGF receptor 1, (C) PDGF receptor-α and (D) VEGF receptor 2.

Figure 4. Comparison of immunohistochemistry markers from individual patient paired samples after adding sorafenib to endocrine therapy (day 1 vs 28)

Biomarkers shown are (A) estrogen receptor, (B) cyclin D1, (C) progesterone receptor and (D) Ki-67. Ki-67 is represented by the percentage of nuclear staining, while estrogen receptor, progesterone receptor and cyclin D1 were scored using the Allred method. Sample numbers correspond to patient numbers in Table 2.

Figure 5. Gene expression heat map representing 33 probe sets for the top 32 genes with an FDR

A list of the 32 genes is provided in Supplementary Table 1, see online at www.futuremedicine.com/doi/suppl/10.2217/fon.14.99. The captions at the top of the figure represent the sequence number of the patient from whom the sample was obtained and whether it was performed on day 1 or 28 (e.g., ‘1_1’ is patient sequence 1 on day 1, ‘1_2’ is patient sequence 1 on day 28, and so on). Patient sequence numbers correspond to the numbers from Table 2.