Assessment and Management of Advanced Adrenocortical Carcinoma Using a Precision Oncology Care Model
AYMEN A. ELFIKY AND HARI K. KRISHNAN NAIR
Abstract: Within the category of orphan diseases and rare malignancies, adrenocortical carcinoma (ACC) represents an aggressive entity with high mortality and morbidity. While localized tumors which are diagnosed early can be cured with surgi- cal intervention, there are prognostic factors which predict for micrometastases and consequent recur- rent and advanced disease. In such cases, cytotoxic chemotherapy and mitotane have been utilized with a very modest degree of benefit. The poor prognosis of recurrent and advanced ACC has underscored the interest in nuanced characterization of ACC cases using next-generation sequencing (NGS)- based genomic and other ‘-omic’ profiling to guide the personalized use of targeted and novel therapies. [Discovery Medicine 21(113):49-56, January 2016]
Clinical Characteristics
Adrenocortical carcinoma (ACC) is a rare and aggres- sive malignancy of the adrenal cortex with an annual US incidence around 1-2 cases per million population (Ng et al., 2003; Hsing et al., 1996; Allolio et al., 2006). Clinical characterization entails stratification of tumors as being ‘functional’ hormone-secreting or ‘non-func- tioning’. Functional tumors represent a minority of about 30% of ACC, although there is a spectrum of functionality. More specifically, secretory tumors pres- ent a clinical syndrome of hormone excess. Approximately 45% of such cases are attributed to the excess glucocorticoids of Cushing’s syndrome, while
Aymen A. Elfiky, M.D., M.A., M.P.H., and Hari K. Krishnan Nair, M.B.B.S.
Dana-Farber Cancer Institute, Brigham and Women’s Hospital; Harvard Medical School, Boston, MA 02215, USA.
Corresponding Author: Aymen A. Elfiky, M.D., M.A., M.P.H. (Aymen_Elfiky@dfci.harvard.edu).
25% present a mixed Cushing’s and virilization syn- drome, with overproduction of both glucocorticoids and androgens (Ng et al., 2003; Wajchenberg et al., 2000). Isolated virilization is seen in less than 10% of ACC cases.
In contrast, non-functioning tumors are more accurately characterized as having subclinical production of steroids, and clinically manifest with pain symptoms in flank or abdomen due to mass effect of progressively growing tumor. Alternatively, such tumors may be inci- dentally noted on radiographic imaging obtained for other non-related causes. Otherwise, constitutional signs or symptoms of anorexia, weight loss, cough, hemoptysis, and so on are likely manifestations of more advanced disease.
While it is not clear whether the hormone-secreting or non-functioning tumors have worse survival outcomes (Hogan et al., 1980; Hough et al., 1979; Abiven et al., 2006), Cushing’s syndrome does cause significant mor- bidity and mortality due to edema, infections, and meta- bolic derangements. On the whole, because of ACC’s rarity and complexity, the prognosis for advanced dis- ease is very poor with a 5-year survival rate lower than 35% in most series (Allolio et al., 2006; Fassnacht et al., 2009; Lughezzani et al., 2010).
Pathogenic Underpinnings
Adrenocortical carcinoma associated with hereditary syndromes
Despite the majority of cases being sporadic, there are well characterized hereditary cancer syndromes which place individuals at risk for ACC (Koch et al., 2002; Sidhu et al., 2004).
Li-Fraumeni syndrome
This is an autosomal dominant familial cancer syn- drome associated with a spectrum of malignancies in
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which ACC appears with a frequency of about 1% (Kamio et al., 1980). TP53 functions to halt the cell cycle and/or induce apoptosis in response to DNA dam- age. Mutations of the TP53 tumor suppressor gene on chromosome 17 results in its inactivation, and are pres- ent in around 70% of patients with Li-Fraumeni syn- drome (Bachinski et al., 2005). Based on the de novo incidence of TP53 mutations in about 25% of patients, genetic testing is recommended for any patient with ACC, even in the absence of family history of cancer (Chompret et al., 2000). The inactivation of TP53 is proposed to follow a ‘two-hit’ mechanism where fol- lowing a germline or somatic inactivating TP53 muta- tion, a second genetic event such as a second somatic mutation, promoter gene methylation or loss of het- erozygosity of the locus is responsible for the inactiva- tion of the second allele (Libe et al., 2007). When sub- sequently considered within the framework of a multi- step tumorigenesis model (Hollstein et al., 1991), the commonality of somatic TP53 mutations in ACC sug- gests TP53 inactivation is a late step in tumorigenesis (Barzon et al., 2001).
Beckwith-Wiedemann syndrome
Beckwith-Wiedemann syndrome (BWS) is associated with abnormalities in 11p15.5 such as parent-of-origin- specific duplications, translocations/inversions, micro- deletions, DNA methylation changes at regulatory regions, and uniparental isodisomy (Weksberg et al., 2010), which are responsible for coding the Insulin Growth-like Factor-2 (IGF-2) and the p57/KIP2 genes. The correlation between BWS and ACC has guided researchers to identify the IGF-2 locus as another nucleotide mutation that is associated with ACC. Patients with sporadic ACC have been found to have a loss of heterozygosity of the IGF-2 gene in 95% of cases (Mazzuco et al., 2012; Smith et al., 2000). The loss of heterozygosity at the IGF-2 locus leads to over- expression of IGF-2, which promotes cell proliferation. However, it is to be noted that how an IGF-2 mutation exactly targets adrenal cortical cells is still undefined. More commonly expressed in ACC, IGF-2 functions to promote progression of disease as opposed to initiating disease (Gicquel et al., 1997; 2001). Its effects are mediated by the insulin-like growth factor 1 receptor (IGFR-1) which is overexpressed in ACCs (Logie et al., 1999). While IGFR-1 demonstrated significant antipro-
| Table 1. Hereditary Syndromes-associated ACC vs. Sporadic ACC. | |
|---|---|
| ACC Associated with Hereditary Syndromes | Sporadic ACC |
| Germline mutations, epigenetic alterations | Allelic losses (loss of heterozygosity), somatic mutations |
| Involved genes: · p53 (Li-Fraumeni syndrome) · Menin tumor suppressor gene (multiple endocrine neoplasia type 1) · PRKAR1A (Carney complex) · IGF2, H19, p57/KIP2 at 11p15 (Beckwith- Wiedemann syndrome) · GNAS1 gene locus (McCune-Albright syndrome) | Involved genes: |
| · p53 | |
| · Menin · PRKARIA | |
| · GNAS1 | |
| · RAS | |
| · IGF-2 | |
| · H19 | |
| · P57/KIP2 | |
| · IGFBP2 | |
| · EGFR | |
| · TGF-a | |
| · FGFR | |
| · MST1R | |
| · TGFRØ | |
| · IL-2Ry | |
| · VEGF | |
| · Ang2 | |
| · Cyclins | |
| · Inhibin A | |
| · novH | |
| · Urotensin II | |
| · Integrin ß2 | |
| · Granzyme A | |
| · SGNE1 | |
| · WISP2 | |
liferative effects in preclinical studies (Almeida et al., 2008; Doghman et al., 2010) and early clinical trials (Haluska et al., 2010), the relatively low overall thera- peutic efficacy precluded the promotion of this treat- ment strategy for ACC.
Carney complex
Carney complex is an autosomal dominant condition, also associated with ACC. Patients with Carney com- plex have a loss of heterozygosity at locus 17q22-24 and 2p16. 17q is the location of the regulatory protein that controls Protein Kinase A (PKA) activity. Loss of PKA control leads to increased cAMP-stimulated activ- ity leading to uncontrolled cell proliferation and is seen in sporadic ACC cases 53% of the time (Koch et al., 2002).
Sporadic adrenocortical carcinoma
Sporadic cases of ACC, in contrast to hereditary syn- dromes, are not as uniformly characterized, but there are pathogenic insights which have been extrapolated from the syndrome-associated cases. Importantly, it is such molecular and genomic findings which can be used to characterize a multistep tumor progression model similar to colon cancer (Koch et al., 2002; Kamio et al., 1990; Bachinski et al., 2005). Analysis of adrenocortical tumors that are known to be associated with hereditary tumor syndromes can provide insights into the genetic and molecular pathways of sporadic adrenocortical tumor formation and progression (Table 1). The researchers suggest that IGF-2 over-expression, loss of heterozygosity of p53, and increased levels of
VEGF all might be linked in some way into a stepwise progression of hyperplasia to adenoma to carcinoma. The example of cortisol hypersecretion which charac- terizes ‘functional’ tumors can be attributed to the aber- rant expression and activation of G-protein coupled receptors. This is a distinction from normal adrenal cor- tex tissue which is characterized by the melanocortin- 2(MC2)-ACTH receptor.
The constitutive activation of beta-catenin in the Wnt signaling pathway, which is essential for embryonic development of the adrenal gland, has also been identi- fied as a frequent alteration in ACC (Kim et al., 2008; Polakis, 2000) with its ectopic constitutive activation being associated with cancer development in a number of tissues (Kikuchi, 2003). Activating mutations of exon 3 of the CTNNB1 gene (beta-catenin) are also fre- quent in adrenocortical tumors (Kikuchi, 2003). In one study, an estimation of about 36% of ACC tumors had CTNNB1 mutations, mostly in larger and nonsecreting adenomas, suggesting further the implication of the Wnt/beta-catenin pathway in the development of less differentiated tumors (Bonnet et al., 2010). Overall, however, somatic CTNNB1 mutations may explain only about 50% of beta-catenin accumulation observed in adrenocortical tumors, indicating that other compo- nents of the Wnt pathway may be involved.
Molecular Pathways and Targeted Therapies
Several molecularly targeted therapies are under study for the treatment of advanced and metastatic ACC. Currently these therapies have only been tested in the context of clinical trials, often after progression of dis-
| Table 2. Targeted Therapies in ACC. | |||
|---|---|---|---|
| Drug | Target | Study Phase / n | Clinical Benefit |
| Sunitinib | VEGF pathway | II / n=35 | 5 patients with SD |
| Sorafenib + Paclitaxel | VEGF pathway + Cytotoxic Chemotherapy | II / n=9 | No Activity |
| Bevacizumab + Capecitabine | VEGF pathway + Cytotoxic Chemotherapy | II / n=10 | No activity |
| Erlotinib + Gemcitabine | EGFR pathway | II / n=10 | 1 patient with SD |
| Gefitinib | EGFR pathway + Cytotoxic Chemotherapy | II / n=19 | No activity |
| Everolimus | mTOR pathway | II / n=4 | No activity |
| Imatinib | C-ABL, PDGFR and C-kit Tyrosine kinase inhibitor | II / n=4 | No activity |
| Cixutumumab (IMC-A12) | IGF-1R pathway | II / n=10 | 1 patient with SD |
| Figitumumab | IGF-1R pathway | I/ n=14 | 8 patients with SD |
| Cixutumumab + Temsirolimus | IGF-1R pathway + mTOR pathway | I/n=10 | 4 patients with SD |
| Abbreviations: VEGF, vascular endothelial growth factor; EGFR, epidermal growth factor receptor; mTOR, mammalian target of rapamycin; IGF-1R, insulin-like growth factor 1 receptor; PDGFR, platelet-derived growth factor receptor. | |||
ease on standard therapies (mitotane or EDP+ mitotane). However, a growing understanding of ACC biology has allowed for the identification of potential pathways and targeted drugs that are being studied in ACC (Table 2; Figure 1).
Classification of ACC Using Genome-wide Expression Profiles
ACC can be differentiated from benign adrenal adeno- mas based on the expression levels of a cluster of genes (de Fraipont et al., 2005) involved in growth factor sig- naling and cell proliferation (Table 3). Gene expression profiles can be correlated with clinical outcome, with the poor outcome group expressing cell cycle genes, functional aneuploidy genes, genes related to transcrip- tional control and mitotic cell cycle (de Reynies et al., 2009). In contrast, the good outcome group express genes involved in cell metabolism, intracellular trans- port, apoptosis and cell differentiation (Figure 2) (de Reynies et al., 2009).
Utilization of “Actionable” Genomic Alterations for Personalized Cancer Treatment
The facilitated use of genomic and classification insights has been getting us closer to the promise of the treatment of individual tumors based on their genetic makeup (Macconaill and Garraway, 2010; Wagle et al., 2012). There are well established clinical use cases which exemplify the impact of actionable molecular insights on disease segmentation and treatment selec- tions. The presence of rearrangement in the ALK (analplastic lymphoma kinase) gene of non-small cell
lung cancers (NSCLC) has directed the use of crizotinib in this cancer sub-population. Crizotinib is an ALK and ROS1 (c-Ros oncogene 1) inhibitor which in an open- label, phase 3 trial comparing crizotinib with standard chemotherapy in patients with advanced, ALK-positive NSCLC showed a significantly longer progression-free survival in favor of crizotinib (Solomon et al., 2014). In a further application of this matching of disease sub- type and clinical manifestations of the disease within a given individual, crizotinib also proved to have a greater reduction in lung cancer symptoms and improvement in quality of life (Solomon et al., 2014). The importance of this added detail, beyond impact on survival metrics, is the option to select a treatment based on an overall palliative goals which take into account a given patient’s physical state, co-morbidities, and goals of care.
Another classic example of molecular targeting trans- lating into precision care is that of advanced colon can- cer. Cetuximab is indicated for the treatment of patients with epidermal growth factor receptor (EGFR)- expressing, KRAS wild-type metastatic colorectal can- cer (mCRC), in combination with chemotherapy. Two large clinical trials provided evidence and guidance on the targeted use and benefit of cetuximab (Bokemeyer et al., 2009; Van Cutsem et al., 2009). Specifically, the detection of KRAS gene mutations helps physicians identify patients that are unlikely to respond to treat- ment with targeted EGFR inhibitors, including cetux- imab and panitumumab. Accordingly, genetic testing to confirm the absence of KRAS mutations, i.e., the pres- ence of the KRAS wild-type gene, is now the clinical standard before the start of treatment with EGFR
Adrenocortical carcinoma
IGF1R Pathway
mTOR Pathway
VEGFR pathway
Anti IGF1R antibody Cixutumumab
IGF1R and insulin receptor inhibitor Linsitinib
mTOR inhibitor Temsirolimus
Anti VEGF antibody Bevacizumab
Selective VEGFR inhibitor Axitinib
Partial responses and disease stabilization
Partial responses and disease stabilization
Temsirolims + Cixutumumab Stable disease in 50%
Very limited therapeutic activity
No response
inhibitors.
Using the above parallels, ‘omic’ disease data provide the necessary range of qualitative and quantitative changes and influences which can characterize ACC throughout the disease trajectory. Moreover, ACC phe- notypes, treatment response, resistance, and outcomes are determined by the combined effects of various fac- tors including molecular disease parameters, patient- specific data, and treatment exposures. To this end, optimized integration provides the potential for deliber- ate and sophisticated assessment of the disease states to tailor more effective treatments (Elfiky et al., 2015). Various methods have been used to study the genetic background and pathogenesis of ACC, with DNA copy number alterations by genomic hybridization, mRNA levels by gene expression profiling and epigenetic alterations by PCR-based methods being the recent methods of molecular analysis of ACC (Sidhu et al., 2002; Soon et al., 2008; de Reynies et al., 2009; Bar- Lev and Annes, 2012; Jain et al., 2012; Lehmann and Wrzesinski, 2012; Assie et al., 2012; Lerario et al., 2014). Comprehensive DNA sequencing of ACC, as opposed to exome sequencing only, using next genera- tion sequencing (NGS)-based genomic profiling has gained interest given the poor prognosis of metastatic ACC patients treated with the ‘gold standard’ of con- ventional chemotherapy and mitotane (Zini et al., 2011). These NGS-based genomic profiles detect
genomic alterations that can be used to guide targeted therapy selection by identifying patients more likely to respond to existing and emerging anticancer regimens (Ross et al., 2014). Gene alterations identified were base substitutions and short indels, gene amplifications, gene homozygous deletions, and gene truncations. In a study of 29 cases of ACC, the common potentially actionable alterations involved NF1, CDKN2A, ATM, CCND2, CDK4, DNMT3A, EGFR, ERBB4, KRAS, MDM2, NRAS, PDGFRB, PIK3CA, PTEN, PTCH1, and STK11 (Table 4) (Ross et al., 2014).
To have an example, what kind of change caused by the genetic alteration that made the targeted therapy possi- ble.
Future Directions
As ‘omics’-based technologies continue to advance, data from genomics, epigenomics, transcriptomics, proteomics, metabolomics, and phenomics will require increasingly integrated analyses to provide insight and knowledge into each patient’s case (Elfiky et al., 2015). Integration of data from the spectrum of growing sources and scales will nurture the needed development of individualized knowledge networks for ACC patients. Ultimately, it is the development of an updat- ed disease taxonomy and ACC systems model across the pathogenic trajectory that will anchor evidence-
| Table 3. Differences between Adrenocortical adenoma and ACC. | ||
|---|---|---|
| Disease Type | Adrenocortical Adenoma | ACC |
| Clonality | Sometimes polyclonal | Monoclonal |
| Ploidy | Diploid | Aneuploid/Polyploid |
| Genomic hybridization | Few regions of chromosomal gains and losses | Complex pattern of chromosomal aberra- tions; multiple regions of gains and losses without a specific pattern |
| Gene expression | Steroidogenic cluster High expression of genes involved in: Steroidogenic machinery | IGF2 cluster High expression of genes involved in: Growth factor signaling Cell proliferation |
| Transcriptional alterations | Aberrant GPCRs expression. Overexpression of PKA target genes and steroidogenic genes. PKA regulatory subunits downregulation. | Upregulation of IGF2, IGF1R, FGFR4, EGFR, telomerase, SPP1, VEGF. Downregulation of CDKN1C, H19 |
| Epigenetics | Promoter methylation | |
| miRNA | Upregulation of miR-184, miR-210, miR- 483, miR-503. Downregulation of miR-214, miR-375, miR-195, miR-355, miR-511. | |
Abbreviations: IGF2, Insulin-like growth factor 2; GPCR, G protein-coupled receptor; PKA, Protein kinase A; IGF1R, Insulin-like growth factor 1 receptor; FGFR4, Fibroblast growth factor receptor 4; EGFR, Epidermal growth factor receptor; SPP1, Secreted phos- phoprotein 1; VEGF, Vascular endothelial growth factor; CDKNIC, Cyclin-dependent kinase inhibitor 1C; H19, gene for a long noncod- ing RNA; miR, MicroRNA.
based practice with causal rather than correlative rela- tionships, in turn facilitating adaptive treatment para- digms.
Disclosure
The authors report no conflicts of interest.
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Adrenocortical Cancer
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Predominance of genes related to:
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Figure 2. Classification of adrenocortical tumors based on clinical outcomes and their corresponding gene alterations.
| Table 4. Targetable Genomic Alterations Discovered by NGS Assessment of ACC. | ||
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| PDGFRB | Amplification | Dasatinib, Imatinib, Sorafenib, Sunitinib |
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