Double-staining Immunohistochemistry Reveals in Malignant Pleural Mesothelioma the Coexpression of ERCC1 and RRM1 as a Frequent Biological Event Related to Poorer Survival

Abstract

Malignant pleural mesothelioma (MPM) is a rare cancer with a poor prognosis. To date, standard MPM therapy is still limited to surgery, radiotherapy, and chemotherapy, including pemetrexed and platinum compounds. The main mechanisms of platinum resistance are associated with DNA repair pathways. Excision repair cross-complementing group 1 (ERCC1) and ribonucleotide reductase subunit M1 (RRM1) are important components of the DNA repair, considered as prognostic and predictive biomarkers in various cancer types. The main goal of the present study was to investigate the ERCC1 and RRM1 expression and their potential impact on outcome in this tumor. A series of 73 MPM, mainly treated with a platin-based regimen, was collected and the immunohistochemistry tests were performed to assess ERCC1 and RRM1 expression. In addition, a multiplex immunohistochemistry has been validated to detect simultaneously the 2 proteins on the same slide. In our series, 36 of 73 cases showed ERCC1 expression and 55 of 73 showed RRM1 expression. The double immunohistochemical staining showed the coexpression of ERCC1/RRM1 in 34 of 73 cases. A significant association between ERCC1 and RRM1 expression was observed in our series (P<0.05). Patients with ERCC1/RRM1 coexpression experienced shorter median overall survival (6.6 vs. 13.8 mo, log-rank=7688; P=0.006). Our results suggest that the coexpression of ERCC1/RRM1 could define a group of MPM patients with the worst prognosis who should need likely alternative treatment. In conclusion, we propose the putative usefulness of ERCC1/RRM1 coexpression as prognostic biomarkers for overall survival in MPM.

RRM1 and ERCC1 as biomarkers in patients with locally advanced and metastatic malignant pleural mesothelioma treated with continuous infusion of low-dose gemcitabine plus cisplatin

“…Patients enrolled at Zimling ZG et al study received either pemetrexed-platinum doublet or vinorelbine-platinum doublet, and only patients that presented a high expression of RRM1 and received vinorelbine showed better response (47.1% vs. 13.3%, negative vs. positive) [21]. Recently, Zito Marino et al, reported thar RRM1 and ERCC1 co-expression was significantly related with worse outcomes in patients with MPM [22]. Even though results from both of these studies contrast with those reported in our present study, it should be underscored that chemotherapy schemes were different to the one we employed.…”

“…We consider that there are two major explanations for the discrepancies observed, the first one is that chemotherapy scheme differ among studies; as previously discussed for RRM1, there is a reasonable possibility that ERCC1 perform different according to the therapy employed; another plausible explanation for the discrepancies observed among studies might be the method employed to quantify ERCC1; while we used the median staining value as the cut-off point for determining high vs low expression, most of the aforementioned studies only used positive vs negative expression for stratifying patients. Accordingly, results are inconsistent among studies, with most studies considering high ERCC1 expression as a factor of worse prognosis [22,30,31].…”

AXL and MET Tyrosine Kinase Receptors Co-Expression as a Potential Therapeutic Target in Malignant Pleural Mesothelioma

“…In recent years, extensive research has focused on the identification of prognostic and predictive markers, however, distinct from other cancers, no target therapies have been currently approved for MPM. The genetic landscape of MPM is characterized by several genetic alterations including the deregulated activation of several signaling pathways, particularly the canonical receptor tyrosine kinase pathways [8,9]. Hmeljak et al proposed a new integrated molecular classification of MPM, showing for the first-time subgroups of MPM from a biological point of view [10].…”