Trends in Endocrinology & Metabolism
ReviewThe next generation of therapies for adrenocortical cancers
Introduction
Adrenocortical carcinoma (ACC) is a disease with an incidence of approximately one patient per million [1], suggesting that many endocrinologists will see patients with this disease rarely, if ever. In common with many endocrine cancers it has a very poor prognosis, with an overall 5-year survival rate around 35% [2]. The poor prognosis is attributable in part to the fact that many ACCs are not detected until they are at advanced stage [3]. However, the cancer behaves aggressively even in tumors detected early, such that cases felt to represent a cure at initial surgery may recur later with metastatic disease. Therapies for ACC have been limited by the ineffectiveness of most cytotoxic chemotherapy regimes, although the adrenolytic agent mitotane produces a response in approximately 25–30% of cases [4]. With the recent explosion of new data on tumor genetics and the renewed interest in targeted signaling pathways using kinase inhibitors, there is reason for guarded optimism regarding the future of ACC treatment. In this review I will discuss the current state of therapies, provide an update on ongoing and recently completely clinical trials, and discuss how therapy for ACC is likely to evolve over the next 5–10 years.
Section snippets
Adrenocortical cancer therapy: the past
The past 50 years has seen the development of chemotherapy regimens that have been beneficial for the treatment of cancer, including diseases such as breast, colon, and hematologic malignancies. As with most endocrine cancers, the response of ACC to classical cytotoxic chemotherapy regimens was poor [5]. Progress in the field was limited by the fact that ACC is rare, and no single institution could accrue enough patients to conduct large randomized trials. Further, the fact that the care of ACC
Formation of the International ACC Working Group
In 1998 Berruti and colleagues in Italy described the use of chemotherapy with etoposide, doxorubicin, and cisplatin together with mitotane (EDP/M, the so-called ‘Berruti’ or ‘Italian’ regimen) [8]. With this combination of agents, 46% of patients achieved a partial response (PR), and 2/28 patients (7.1%) achieved a complete response (CR); these results were confirmed in a follow-up study on 72 patients, including 28 from the original study [9]. Around the same time, Khan and coworkers in
Initiation of molecular analysis of ACC
Another significant development of the past 10 years has been the advent of platform technologies. Although overexpression of insulin-like growth factor 2 (IGF2) in ACC had been known since the mid-1990s from the work of Gicquel, Le Bouc, and colleagues [23], the use of high-throughput techniques has allowed substantial refinement of this information. Adrenocortical tumor mRNA expression-profiling was first carried out by Giordano et al. in 2003 [24], and has been followed by similar studies
Combination therapy
Although the initial development of new therapies has typically been carried out using single-agent trials, past experience indicates that combination therapy is likely to provide additional benefit. This synergy may be realized by simultaneously blocking multiple pathways required for tumor growth/survival, or it may occur by the prevention of resistance to single pathway agents [90].
One of the best documented examples of receptor co-signaling involves EGFR and IGF1R [91]. It is well
Concluding remarks
Although the prognosis for patients with ACC remains guarded, data from the past 10 years have begun to show signs of progress. There is a much improved vision of the signaling pathways that drive ACC, and this is now being matched by new therapeutics that might inhibit these pathways.
In the setting of this optimism, there are important questions which remain and should continue to drive research into ACC (Box 2). First, newer technologies have enabled the identification of serum and tissue
Note added in proof
The FIRM-ACT study was published online in the New England Journal of Medicine on May 2, 2012. As noted in the text, EDP/M was found to be superior to Sz/M, with response rates of 23.2% and 9.2% respectively. Treatment recommendations remain as described in Box 1.
Glossary
- Adjuvant chemotherapy
- a pharmacological or immunological agent that is administered in the absence of known cancer but is presumed to act by treating residual microscopic disease.
- Adrenolytic agent
- an agent that acts by destroying adrenal cells.
- EDP/M combination therapy
- also called the ‘Berruti’ or ‘Italian’ regimen, this chemotherapy protocol for ACC combines the use of the anti-cancer chemotherapy drugs etoposide (a topoisomerase inhibitor), doxorubicin (an anthracycline) and cisplatin (a
References (99)
The Italian Registry for Adrenal Cortical Carcinoma: analysis of a multiinstitutional series of 129 patients. The ACC Italian Registry Study Group
Surgery
(1996)- et al.
Adrenocortical carcinoma: diagnosis, evaluation and treatment
J. Urol.
(2003) - et al.
Practical considerations in the evaluation and management of adrenocortical cancer
Semin. Oncol.
(2010) Adjuvant and definitive radiotherapy for adrenocortical carcinoma
Int. J. Radiat. Oncol. Biol. Phys.
(2011)Percutaneous laser ablation of unresectable primary and metastatic adrenocortical carcinoma
Eur. J. Radiol.
(2008)Distinct transcriptional profiles of adrenocortical tumors uncovered by DNA microarray analysis
Am. J. Pathol.
(2003)Expression profiling of adrenocortical neoplasms suggests a molecular signature of malignancy
Surgery
(2005)- et al.
Defining the pathway to insulin-like growth factor system targeting in cancer
Biochem. Pharmacol.
(2010) Immunohistochemical expression of epidermal growth factor receptors in human adrenocortical carcinoma
Hum. Pathol.
(1990)Epidermal growth factor receptor in adrenocortical tumors: analysis of gene sequence, protein expression and correlation with clinical outcome
Mod. Pathol.
(2010)
Sustained remission with the kinase inhibitor sorafenib in stage IV metastatic adrenocortical carcinoma
Endocr. Pract.
Akt-dependent and -independent mechanisms of mTOR regulation in cancer
Cell. Signal.
The Wnt/beta-catenin signaling pathway as a target in drug discovery
J. Pharmacol. Sci.
Rosiglitazone induces autophagy in H295R and cell cycle deregulation in SW13 adrenocortical cancer cells
Exp. Cell Res.
The European Network for the Study of Adrenal Tumors staging system is prognostically superior to the international union against cancer-staging system: a North American validation
Eur. J. Cancer
Clinical review: prevalence and incidence of endocrine and metabolic disorders in the United States: a comprehensive review
J. Clin. Endocrinol. Metab.
Mitotane for adrenocortical carcinoma treatment
Curr. Opin. Investig. Drugs
Adrenal cortical carcinoma
J. Urol.
Management of patients with adrenal cancer: recommendations of an international consensus conference
Endocr. Relat. Cancer
A debate on laparoscopic versus open adrenalectomy for adrenocortical carcinoma
Horm. Cancer
Mitotane associated with etoposide, doxorubicin, and cisplatin in the treatment of advanced adrenocortical carcinoma. Italian Group for the Study of Adrenal Cancer
Cancer
Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase II trial
Endocr. Relat. Cancer
Streptozocin and o,p’DDD in the treatment of adrenocortical cancer patients: long-term survival in its adjuvant use
Ann. Oncol.
Etoposide, doxorubicin, cisplatin, and mitotane vs. streptozotocin and mitotane in adrenocortical carcinoma – (preliminary) results of the FIRM-ACT trial
Endocr. Rev.
Low-dose monitored mitotane treatment achieves the therapeutic range with manageable side effects in patients with adrenocortical cancer
J. Clin. Endocrinol. Metab.
Adjuvant mitotane treatment for adrenocortical carcinoma
N. Engl. J. Med.
Adrenocortical carcinoma: a clinician's update
Nat. Rev. Endocrinol.
Approach to the patient with adrenocortical carcinoma
J. Clin. Endocrinol. Metab.
Radiotherapy in adrenocortical carcinoma
Cancer
Efficacy of adjuvant radiotherapy of the tumor bed on local recurrence of adrenocortical carcinoma
J. Clin. Endocrinol. Metab.
Liver resection and ablation for metastatic adrenocortical carcinoma
Ann. Surg. Oncol.
Radiofrequency ablation for adrenal lesions
Curr. Urol. Rep.
Rearrangements at the 11p15 locus and overexpression of insulin-like growth factor-II gene in sporadic adrenocortical tumors
J. Clin. Endocrinol. Metab.
Gene expression profiling of human adrenocortical tumors using complementary deoxyribonucleic acid microarrays identifies several candidate genes as markers of malignancy
J. Clin. Endocrinol. Metab.
Analysis by cDNA microarrays of gene expression patterns of human adrenocortical tumors
Eur. J. Endocrinol.
Gene expression profiling reveals a new classification of adrenocortical tumors and identifies molecular predictors of malignancy and survival
J. Clin. Oncol.
Beta-catenin activation is associated with specific clinical and pathologic characteristics and a poor outcome in adrenocortical carcinoma
Clin. Cancer Res.
Characterization of differential gene expression in adrenocortical tumors harboring beta-catenin (CTNNB1) mutations
J. Clin. Endocrinol. Metab.
MicroRNA profiling of adrenocortical tumors reveals miR-483 as a marker of malignancy
Cancer
The role of microRNA deregulation in the pathogenesis of adrenocortical carcinoma
Endocr. Relat. Cancer
Integrative molecular bioinformatics study of human adrenocortical tumors: microRNA, tissue-specific target prediction, and pathway analysis
Endocr. Relat. Cancer
Preclinical targeting of the type I insulin-like growth factor receptor in adrenocortical carcinoma
J. Clin. Endocrinol. Metab.
Safety, tolerability, and pharmacokinetics of the anti-IGF-1R monoclonal antibody figitumumab in patients with refractory adrenocortical carcinoma
Cancer Chemother. Pharmacol.
Novel anticancer targets: revisiting ERBB2 and discovering ERBB3
Nat. Rev. Cancer
Transforming growth factor alpha, epidermal growth factor, and epidermal growth factor receptor expression in normal and diseased human adrenal cortex by immunohistochemistry and in situ hybridization
Mod. Pathol.
HER2: biology, detection, and clinical implications
Arch. Pathol. Lab. Med.
One target, different effects: a comparison of distinct therapeutic antibodies against the same targets
Exp. Mol. Med.
A phase II trial of gefitinib monotherapy in patients with unresectable adrenocortical carcinoma (ACC)
J. Clin. Oncol.
Treatment of advanced adrenocortical carcinoma with erlotinib plus gemcitabine
J. Clin. Endocrinol. Metab.
Cited by (19)
Inhibition of IGF-1R in adrenocortical carcinoma
2015, The Lancet OncologyAdrenocortical carcinoma: The management of metastatic disease
2014, Critical Reviews in Oncology/HematologyCitation Excerpt :Similarly, it activates RAS and extracellular-signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway leading to tumor growth and proliferation [80]. Cixutumumab (IMC-A12) and figitumumab (CP-751,871) are IGF-IR-targeting antibodies currently in development to block the interaction between IGF-IR and its ligand [81]. Figitumumab was evaluated in a phase I study which enrolled 14 patients with advanced ACC.
Lack of long-lasting effects of mitotane adjuvant therapy in a mouse xenograft model of adrenocortical carcinoma
2013, Molecular and Cellular EndocrinologyCitation Excerpt :Our results show that mitotane adjuvant therapy is inadequate to antagonize long-term growth of H295R cancer cell xenografts in immunodeficient mice and that care should then be taken in the design of preclinical protocols to evaluate the performance of new drugs (Kirschner, 2012) in association with mitotane in those animal models.
Adrenal carcinoma: A retrospective analysis of our series
2013, Endocrinologia y NutricionTranslational Research in Endocrine Surgery
2013, Surgical Oncology Clinics of North AmericaCitation Excerpt :Patients with Beckwith-Widemann syndrome (BWS) are prone to ACC,122 and the chromosomal region 11p15.5 that is altered in BWS contains IGF2, and is also altered in sporadic ACC.123 At this parentally imprinted locus, duplications, deletions, gene methylation, chromosomal loss, and uniparental disomy cause variations in the effective copy number of IGF2, with increased gene dosage driving proliferation and malignancy in neural crest–derived tissues.122,124 High expression of IGF2 also correlates with earlier recurrence in ACC.125
Nomograms for Individualized Evaluation of Prognosis in Adrenocortical Carcinomas for the Elderly: A Population-Based Analysis
2022, Journal of Investigative Surgery