Percentage genome change and chromosome 7q amplification predict sorafenib response in advanced hepatocellular carcinoma

Abstract

Background: Hepatocellular carcinoma (HCC) may arise from genomic instability and has dismal outcome. Sorafenib is the first-line treatment for advanced stage HCC, but its therapeutic efficacy is less than 50%. Biomarkers for predicting the therapeutic efficacy of sorafenib administration to patients with advanced HCC are required. Here, we evaluated the role of chromosomal copy number aberrations (CNAs) in patients with advanced HCC who were treated with sorafenib along with their drug response.

Methods: The response to sorafenib treatment of twenty-three HCC patients who developed advanced recurrence after partial hepatectomy was analyzed using the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Formalin fixed paraffin embedded (FFPE) tissue specimens obtained after tumor resection were analyzed using the Affymetrix OncoScan® FFPE assay.

Results: From the 23 patients analyzed in this study, 7 (30.4%) had complete/partial response to sorafenib (CR/PR), 7 (30.4%) had stable disease (SD), and 9 (39.1%) had progressive disease (PD). The mean genome-wide percentage of genome change acquisition via the OncoScan platform was 19.8% for patients with CR/PR/SD and 50.02% in the PD group (p = 0.055). Percentage of genome change above 33% was associated with adverse outcomes for sorafenib treatment in the time-to-progression analysis (p = 0.007) and overall survival (p = 0.096). Among these CNAs, amplification of chromosome 7q, containing the multidrug resistance gene ATP Binding Cassette Subfamily B Member 1 (ACBC1), significantly associated with poor overall survival (p = 0.004) and time-to-progression (p < 0.001).

Conclusions: Higher percentage genome change and amplification of chromosome 7q in advanced HCC is associated with sorafenib resistance.

Keywords: 7q amplification; ABCB1; Advanced HCC; Copy number aberrations; Sorafenib.

Fig. 1

Clinical treatment of HCC at advanced stage. (A) No. 23, 74 y/o male, developed sternum and liver recurrence. He had complete treatment response to sorafenib, radiotherapy, and TACE. He had been off treatment for 5 years or more. (B) No. 18, 42 y/o female, had regional lymph node metastasis and failed local ablation treatment, but she received a 200–400 mg daily dosage of sorafenib to keep her condition stable. The best response was a partial response. (C) 56 y/o male, had right scapula metastatic destruction and progressive disease. The target lesion is marked with white and black arrows before and 3 months after treatment in the computed tomography scans, respectively. (D) Cumulative survival rates of advanced HCC with sorafenib administration and the log-rank test indicated a better outcome when the treatment was complete/partial response (CR/PR) (tumor shrinkage, black solid line) as compared with stable disease/progressive disease (SD/PD) (gray dotted line) (p = 0.003).

Fig. 2

The global chromosomal change in clinical sorafenib treatment for HCC. There was a remarkable increase in CNAs for the treatment response from CR/PR (A) to SD (B) to PD (C). There was significant increase of amplification at chromosome 7q that was associated with sorafenib resistance (Black arrow).

Fig. 3

The percentage genome change and amplification of chromosome 7q in overall survival and time-to progression analysis (A). The cut-off of percentage genome change for outcome prediction was set at ≤33.0% vs. >33.0% and the log-rank test showed no significant difference although it showed a tendency for the same (p = 0.096). (B) The time-to-progression analysis indicated a significantly better outcome when percentage genome change was <33% (black solid line) (p = 0.004). (C) The amplification of chromosome 7q (dotted line) was significantly associated with poor outcome in overall survival (p = 0.004). (D) The amplification of chromosome 7q (dotted line) was significantly associated with poor survival in the time-to progression analysis. (p < 0.001).

Fig. 4

The expression of ABCB1, EGFR and BRAF in four representative cases were examined via immunohistochemistry in tumor FFPE specimen. The copy number changes in each gene within patient was as described. Amp: amplification (copy number >2), normal (copy number = 2). The staining density of ABCB1, EGFR was higher in specimen with copy number amplification than those are without amplification. The magnification of left three panel was 100X; whereas the magnification of the right panel (BRAF) was 200X.