Decrease of survivin, p53 and Bcl-2 expression in chemorefractory colorectal liver metastases may be predictive of radiosensivity after radioembolization with yttrium-90 resin microspheres

Elisa Melucci,Francesco Fiore,Maria Grazia Diodoro,Francesco Izzo,Rosa Sciuto,Rita Golfieri,Raffaello Mancini,Marcella Mottolese,Maurizio Cosimelli,Emanuela Giampalma,Carlo Garufi,Livio Carpanese,Cristiana Ercolani,Isabella Sperduti,Giuseppe Pizzi

doi:10.1186/1756-9966-32-13

Abstract

In a prospective multicenter phase II trial of radioembolization with yttrium-90 (90Y-RE) in chemorefractory liver-dominant metastatic colorectal cancer (mCRC), we showed that median survival was 12.6 months (95% CI 7.0–18.3) with 48% of 50 patients achieving disease control. In this extension retrospective study, we analyzed whether a panel of biomarkers, known to be associated to an adverse clinical outcome, underwent variations in CRC liver metastases pre and post 90Y-RE.Of the 50 patients included in the study, 29 pre-90Y-RE therapy and 15 post-90Y-RE had liver biopsy specimens available. In these series we investigated survivin, p53, Bcl-2 and Ki-67 expression pre- and post-90Y-RE by immuhistochemistry (IHC). Our findings evidenced a decrease of survivin (77% vs 33%), p53 (93% vs 73%), Bcl-2 (37% vs 26%) expression as well as of Ki-67 proliferation index (62.5% vs 40%) on liver biopsies collected post-90Y-RE as compared to pre-90Y-RE. In the subset of 13 matched liver metastases we further confirmed the reduction of survivin (92.3% vs 53.8%; p = 0.06), p53 (100% vs 69.2%; p = 0.05) and Bcl-2 (69.2% vs 53.8%; p = 0.05) expression post-90Y-RE. This biomarker modulation was accompanied by morphological changes as steatohepatitis, hepatocyte necrosis, collagen deposition, proliferating and/or bile duct ectasia, focal sinusoidal dilatation and fibrosis.Although our analysis was conducted in a very limited number cases, these changes appear strictly related to the response to 90Y-RE therapy and may deserve further investigation on a larger series of patients.

Highlights

Liver metastases are a significant cause of morbidity and mortality for more than 45% of patients who present with colorectal cancer (CRC) [1]
Expression pattern of survivin, p53, Bcl-2 and Ki-67 in liver metastases pre- and post-90Y-RE Of the 50 patients included in the Society of Locoregional Therapy in Oncology (SITILO) clinical trial, 29 pre-90Y-RE and 15 post-90Y-RE had sufficient tissue material from their liver metastases for IHC evaluation of survivin, p53, Bcl-2 and Ki-67
Of the 15 liver metastases available post-90Y-RE, survivin was expressed in 5 cases (33.3%), p53 in 11 (73.3%), Bcl2 in 4 (26.7%) and Ki-67 was high in 6 lesions (40.0%) evidencing a variation in biomarker expression pre and post-90Y-RE

Summary

Introduction

Liver metastases are a significant cause of morbidity and mortality for more than 45% of patients who present with colorectal cancer (CRC) [1]. In the setting of clinical trials, median overall survival for unresectable metastases have been extended beyond two years using combinations including oxaliplatin, irinotecan, capecitabine and biologic agents (bevacizumab, cetuximab, panitumumab) [3,4] In parallel with these developments, the application of locally ablative procedures, such as radiofrequency ablation, are increasingly considered beneficial for patients with unresectable liver-only disease who present with tumors ≤ 3–4 cm in diameter. These regional treatments for liver metastases can be used to consolidate the treatment response with chemotherapy, in order to further increase the number of patients eligible for resection [5,6]. One of the major challenges in advanced CRC are the growing proportion of patients who continue to present with progressive liver involvement having exhausted all other therapeutic options

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