Expression of excision repair cross complementing group 1 and prognosis in adrenocortical carcinoma patients treated with platinum-based chemotherapy

Abstract

Therapeutic progress in adrenocortical carcinoma (ACC) is severely hampered by its low incidence. Platinum-based chemotherapies are the most effective cytotoxic treatment regimens in ACC but response rates remain !50%. In other tumor entities, expression of excision repair cross complementing group 1 (ERCC1) predicts resistance to platinum compounds. Therefore, we correlated ERCC1 protein expression and clinical outcome. We have retrolectively established adrenal tissue microarrays and analyzed prospectively samples from 163 ACCs, 15 benign adrenal adenomas, and 8 normal adrenal glands by immunohistochemistry for ERCC1 protein expression. Detailed clinical data were available by the German ACC Registry. ERCC1 protein was highly expressed in all normal adrenal glands, 14 benign tumors (93%) and in 75 ACCs (47%). In ACC, no differences in baseline parameters were found between patients with and without ERCC1 expression. Detection of ERCC1 was not correlated with survival in patients who never received platinum-based chemotherapy. In platinum-treated patients (nZ45), objective response to platinum compounds was observed in 3/21 patients (14.3%) with high ERCC1 expression and in 7/24 patients (29.2%) with low ERCC1 expression (PZ0.23). ERCC1 expression was strongly correlated with overall survival after platinum treatment (median: eight months in patients with high ERCC1 versus 24 months in low ERCC1 expression, hazard ratio (HR) 2.95 (95% confidence interval (CI) 1.4-6.2), PZ0.004). Multivariate analysis confirmed that high ERCC1 expression was a predictive factor for poor prognosis in platinum treated patients (HR 2.2, 95% CI 1.0-4.5, PZ0.038). Our findings suggest that ERCC1 expression is the first factor for predicting survival in ACC patients treated with platinum-based chemotherapy.

Linsitinib (OSI-906) versus placebo for patients with locally advanced or metastatic adrenocortical carcinoma: a double-blind, randomised, phase 3 study

“…22 No particular signature for response to IGF-1R inhibition has yet been identified in ACC. A possible negative impact on response to platinum-based therapies has been found for high expression levels of the DNA repair gene excision repair complementation group 1 (ERCC1), 23 and high ribonucleotide reductase large subunit (RRM1) gene expression had some association with poor efficacy of adjuvant mitotane therapy. 24 As expected, the pharmacokinetic profile of linsitinib was similar to that observed in a dosedetermining phase 1 study, with rapid absorption after oral dose and accumulation following continuous twice-daily dosing.…”

Future directions in the diagnosis and medical treatment of adrenocortical carcinoma

“…As a possible mechanism, Germano et al (2015) showed that the RRM1 gene interferes with mitotane metabolism in ACC cells. Ronchi et al (2009) investigated protein expression of excision repair cross complementing group 1 (ERCC1) as a predictor for response to platinum-based chemotherapy in patients with ACC. High ERCC1 expression was correlated with a worse overall survival in patients treated with platinum-based chemotherapy.…”

Epidermal growth factor receptor in adrenocortical tumors: analysis of gene sequence, protein expression and correlation with clinical outcome

“…[35][36][37] Briefly, hematoxylin and eosin-stained sections of formalin-fixed and paraffin-embedded tissue blocks were evaluated to identify representative areas of well-preserved morphology. The corresponding area on the paraffin block was marked for tissue punching.…”