Abstract
Mitotane is the most broadly used systemic therapy for adrenocortical carcinoma (ACC), but its mechanism of action and possible predictors of treatment response are currently poorly defined. Our aim was to evaluate the gene expression of ribonucleotide reductase large subunit 1 (RRM1) and excision repair cross-complementation group 1 (ERCC1) in ACC as potential biomarkers for clinical outcome and response to mitotane. Forty-five and 47 tissue samples from two cohorts (Orbassano, Italy; Wuerzburg, Germany) of completely resected ACC were centrally analyzed using real-time PCR for RRM1 and ERCC1 expression. Fifty-four patients received surgery alone and 38 received adjuvant mitotane after surgery. Clinical and pathologic features were highly comparable in the two series. H295R and SW-13 ACC cell lines were also used for pharmacologic tests. ERCC1 gene expression was not associated to clinical outcome. In contrast, high RRM1 gene expression was associated to shorter disease-free survival (DFS) and overall survival at both univariate and multivariate analysis. In patients with low RRM1 gene expression, adjuvant mitotane was associated with improved DFS, whereas this effect was lost in cases with high RMM1 expression. In vitro mitotane induced strong up regulation of RRM1 transcription (up to 25-fold increase) in mitotane-insensitive SW-13 but not in mitotane-sensitive H295R cells. Furthermore, RRM1 silencing in SW-13 cells induced sensitivity to mitotane. Our in vitro and in vivo data indicate that RRM1 gene expression is functionally associated to mitotane sensitivity and support a possible role of RRM1 determination as a novel molecular biomarker predicting response to adjuvant mitotane in ACC.
Highlights
Adrenocortical carcinoma (ACC) is a rare and aggressive malignant tumor.[1,2] Surgery is the mainstay of therapy,[3,4] medical treatment has an important role because a large proportion of adrenocortical carcinoma (ACC) patients presents with metastatic disease and most of the radically resected patients relapse after surgery, often with metastases.[5]
Mitotane treated patients had a longer DFS than patients followed up only: median 22.5 months [95% confidence interval (CI) 1.8-43.1] versus 13.2 months, Hazard Ratio (HR) 0.70, and longer overall survival; median 154 months versus 53 months, Hazard ratios (HR) 0.63
Mitotane has been shown to sensitize H295R and SW-13 ACC cells to ionizing radiations by attenuating DNA repair and interfering with cell proliferation,[40] data suggesting that mitotane, in addition to the assumed binding to proteins and phospholipids, may interact with DNA, as was previously demonstrated in vitro.[41]
Summary
Adrenocortical carcinoma (ACC) is a rare and aggressive malignant tumor.[1,2] Surgery is the mainstay of therapy,[3,4] medical treatment has an important role because a large proportion of ACC patients presents with metastatic disease and most of the radically resected patients relapse after surgery, often with metastases.[5]. A single study reported that a low immunohistochemical expression of excision repair cross-complementation group 1 (ERCC1) correlated to objective response and overall survival in ACC patients treated with platinum-based chemotherapy.[19] Concerning mitotane treatment, attainment of drug levels in the target range of 14-20 mg/L is the only factor predicting efficacy that has been convincingly demonstrated.[20,21,22] Since most ACC patients are at high risk of recurrence after primary surgery applying current prognostication methods,[9] selection of patients for adjuvant therapy with mitotane based upon predictive factors for drug efficacy may represent a superior approach than selection based on prognostic markers. We analyzed the predictive role of these two markers in patients treated with adjuvant mitotane and strengthened the in vivo results by in vitro analysis on ACC cell lines
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