Exploring the latest research and treatments for adrenocortical carcinoma, a rare but aggressive cancer of the adrenal glands.
In a quiet conference room at MD Anderson Cancer Center, a group of international scientists, physicians, and patients gathered in November 2024 with one shared hope: better treatments for the devastating disease of adrenocortical carcinoma. This rare but aggressive cancer, often discovered by chance, has long puzzled researchers and clinicians alike 1 .
Perched atop our kidneys like tiny tri-cornered hats, the adrenal glands may be small, but they wield enormous power over our bodies. These unsung heroes produce hormones that regulate everything from how we handle stress to maintaining our blood pressure and metabolism.
Adrenocortical carcinoma (ACC) is remarkably rare—affecting roughly 1 in 1 million people annually—but its impact is profound 2 . What makes this cancer particularly insidious is its dual threat: it can grow large enough to press on vital organs while potentially flooding the system with uncontrolled amounts of hormones 2 .
For decades, treatment options have remained limited, with only one drug specifically approved for this disease. But recent scientific advances are beginning to illuminate the path toward better outcomes.
ACC affects only 1-2 people per million annually, making it one of the rarest cancers.
Many patients are diagnosed at advanced stages when the cancer has already spread.
The adrenal gland consists of two main parts with different functions. The inner adrenal medulla produces catecholamines like adrenaline that govern our "fight-or-flight" response. The outer adrenal cortex, where ACC originates, produces three critical types of steroid hormones:
(including cortisol) that regulate carbohydrate, protein, and fat metabolism
(primarily aldosterone) that maintain fluid balance through sodium and potassium regulation
that influence sexual development and function 3
When adrenocortical carcinoma develops, it can be "functioning" (releasing excess hormones) or "non-functioning" (not affecting hormone production). Approximately 48% of ACCs are hormonally active, and these functioning tumors often carry a worse prognosis 4 .
ACC is biologically aggressive because tumors can grow quickly and spread to distant organs like the lungs and bones 2 . The cancer staging system reveals how progressively serious the disease becomes:
| Stage | Tumor Characteristics | 5-Year Survival Rate |
|---|---|---|
| Stage I | Tumor ≤5 cm, confined to adrenal gland |
|
| Stage II | Tumor >5 cm, confined to adrenal gland |
|
| Stage III | Tumor spread to nearby lymph nodes |
|
| Stage IV | Tumor spread to distant organs |
|
Data from 2
Unfortunately, many patients are diagnosed at later stages (III or IV) when the cancer has already spread beyond the adrenal gland, making curative treatment more challenging 1 .
Researchers have identified key genetic drivers behind adrenocortical carcinoma. While many cases appear sporadically, some occur in people with inherited cancer syndromes 3 .
The molecular pathogenesis of ACC involves several critical genetic pathways:
This crucial gene, known as the "guardian of the genome," is mutated in a significant number of ACC cases. When functioning properly, TP53 helps prevent cancerous growth by regulating cell division and triggering programmed cell death in damaged cells. In ACC, TP53 mutations are associated with more aggressive tumors and poorer outcomes 3 .
Approximately 30% of ACC patients have alterations in this pathway, which normally helps regulate cell growth and specialization. When dysregulated, it can drive uncontrolled tumor growth 1 .
Recently identified as the most frequently altered gene in ACC, appearing in 19-21% of cases. ZNRF3 normally acts as a tumor suppressor by helping degrade receptors that activate the Wnt signaling pathway 3 .
This growth factor is commonly overexpressed in ACC, driving cell proliferation and tumor growth. IGF2 overexpression is one of the most consistent molecular findings in adrenocortical carcinoma.
| Gene/Pathway | Function | Role in ACC | Frequency in ACC |
|---|---|---|---|
| TP53 | Tumor suppressor, DNA repair | Loss of function leads to uncontrolled growth | 16-70% of cases |
| Wnt/β-catenin | Cell growth regulation | Constitutive activation promotes tumor development | ~30% of cases |
| ZNRF3 | Negative regulator of Wnt signaling | Loss of function activates Wnt pathway | 19-21% of cases |
| IGF2 | Growth factor | Overexpression drives cell proliferation | Commonly overexpressed |
Several inherited conditions increase ACC risk:
Caused by TP53 germline mutations dramatically increases ACC risk, particularly in children in Southern Brazil where a specific TP53 mutation (p.R337H) is common 3 .
From APC gene mutations increases risk of various cancers, with adrenocortical tumors occurring in 7-13% of affected individuals 3 .
Involves genetic and epigenetic changes at chromosome 11p15.5 that predispose to several cancers, including ACC 3 .
With limited treatment options for advanced ACC, researchers at MD Anderson Cancer Center designed a pioneering Phase II clinical trial to test cabozantinib, an antiangiogenic multi-tyrosine kinase inhibitor that blocks several pathways involved in cancer growth 5 .
This was particularly important for rare cancers like ACC, which are difficult to study in large clinical trials due to small patient numbers. Before this, only one drug (mitotane) was FDA-approved for ACC, highlighting the urgent need for more therapeutic options 5 .
The trial enrolled 18 patients with advanced adrenocortical carcinoma who had progressed on prior treatments 5 .
Participants received cabozantinib according to a predetermined dosing schedule, with careful monitoring for side effects and toxicity 5 .
Researchers regularly evaluated patients using imaging scans, progression-free survival as the primary endpoint, and safety assessments 5 .
Patients were monitored for treatment response over time, with data analyzed to determine the drug's effectiveness 5 .
The findings, published in The Lancet Oncology in 2024, demonstrated encouraging results:
of patients (13 of 18) achieved progression-free survival longer than four months 5
safety profile consistent with cabozantinib use in other cancer types 5
established that cabozantinib has meaningful anti-tumor activity in ACC 5
| Outcome Measure | Result | Significance |
|---|---|---|
| 4-Month Progression-Free Survival | 72% (13/18 patients) | Exceeded predefined threshold for success |
| Overall Response Rate | Data not specified in source | Demonstrated antitumor activity |
| Safety Profile | Manageable side effects | Consistent with known cabozantinib toxicity |
| Recommended Application | Support for combination therapy trials | Suggests pairing with immunotherapy |
Data from 5
This study was significant for several reasons:
It represented the first prospective Phase II study of cabozantinib specifically for ACC, providing valuable high-quality evidence for this rare cancer 5 .
The results support further investigation of cabozantinib in combination with immune checkpoint inhibitors, potentially opening doors to more effective combination therapies 5 .
The trial demonstrated that meaningful research is possible even for rare cancers through carefully designed studies 5 .
Understanding ACC requires specialized tools and reagents that enable researchers to unravel its complexities:
| Reagent/Resource | Function in ACC Research | Application Example |
|---|---|---|
| Patient-Derived Xenograft (PDX) Models | Implant human ACC tumors into mice for study | Creating models that accurately represent human disease for drug testing 5 |
| Mitotane | Adrenolytic agent inhibits adrenal activity | Standard treatment after surgery; research on mechanisms of action and resistance 6 2 |
| Immune Checkpoint Inhibitors | Block proteins that prevent immune system attack on cancer | Testing combination therapies (e.g., pembrolizumab + lenvatinib) 7 |
| Whole Genome Sequencing | Comprehensive analysis of genetic alterations | Identifying mutations in TP53, ZNRF3, CTNNB1, and other ACC drivers 3 |
| Histopathological Stains | Visualize tissue architecture and cell features | Determining Weiss score (≥3 indicates malignancy) 3 |
| CTNNB1 Mutational Analysis | Detect mutations in β-catenin gene | Investigating Wnt pathway activation in ACC 3 |
The current approach to ACC management includes:
Complete removal of the affected adrenal gland (adrenalectomy) offers the best chance for cure, especially in early-stage disease 2 .
The combination of etoposide, doxorubicin, and cisplatin with mitotane serves as first-line treatment for advanced disease, achieving response rates of approximately 23% in the pivotal FIRM-ACT trial 1 .
Techniques like thermal ablation, transarterial embolization, and radiotherapy help control localized tumor growth, with complete response achieved in 21% of treated lesions in one recent study 8 .
The future of ACC treatment looks promising with several innovative approaches:
Ongoing trials are testing combinations like lenvatinib with pembrolizumab and cabozantinib with atezolizumab, leveraging synergistic effects between different drug classes 7 .
Investigations into factors like mitotane plasma levels (>14 mg/L positively influences outcomes) and molecular signatures aim to personalize treatment approaches 8 .
Adrenocortical carcinoma remains a challenging disease, but the scientific landscape is transforming. From the early days of having only mitotane as a specific treatment, we're now entering an era of targeted therapies, immunotherapies, and precision medicine approaches.
The international collaboration epitomized by gatherings like the International Adrenal Cancer Symposium continues to drive progress. As one researcher noted, cases of successful treatment responses—including a remarkable case of neoadjuvant combination immunotherapy leading to successful resection with no evidence of disease a year later—"offer a glimmer of hope for this rare disease" 1 .
While ACC may always be a formidable opponent, the growing understanding of its genetic underpinnings, combined with innovative treatment strategies, provides genuine optimism for patients and clinicians alike. The hidden gland is gradually revealing its secrets, and with each discovery comes the potential for longer, better lives for those affected by this rare cancer.
This article synthesizes information from peer-reviewed scientific literature and clinical resources to provide an accurate overview of current knowledge about adrenocortical carcinoma. Treatment decisions should always be made in consultation with healthcare professionals.