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Therapeutic frontiers in adrenocortical carcinoma: from standards to innovation
Dylan M. Schaap1 . Emily X. Jie1 . Trenton G. Mayberry2 . Braydon C. Cowan2 . Mark R. Wakefield2,3 . Yujiang Fang1,2,3
Received: 1 April 2025 / Accepted: 12 June 2025 / Published online: 3 July 2025 @ The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2025
Abstract
Cancer remains the second leading cause of death in America despite cancer-related mortality declining. Adrenocortical carcinoma (ACC) is a rare but aggressive cancer with a poor prognosis that imposes an immense burden on those ill-fated to be touched by this cancer. The 5-year survival rate is below 50% for locally advanced cases, and nearly 75% of patients experi- ence recurrence. Surgical resection is the only curative option, while radiation therapy may be beneficial post-adrenalectomy or in select cases. Mitotane, alone or with etoposide, doxorubicin, and cisplatin, is the primary chemotherapy for advanced or inoperable disease. Immunotherapy is emerging as a promising treatment for advanced ACC due to its proven effective- ness in other cancers. There is still a plethora of new and undiscovered prognostic and pharmaceutical targets for ACC that researchers are investigating. This review explores current and evolving ACC treatments, including surgery, radiotherapy, chemotherapy, and immunotherapy, to aid clinicians in patient management.
Keywords Adrenocortical carcinoma · Treatment . Mitotane . Adrenalectomy . Immunotherapy
Introduction
Atop each kidney, the adrenal glands play a critical role in hormone production and regulation of many bodily func- tions. However, there are severe consequences when malig- nant tumors arise within them, particularly adrenocortical carcinoma (ACC). This is a rare malignancy with an age- adjusted incidence of approximately 1 case per million in the United States and a reported 0.7 to 2 cases per million per year globally [1, 2]. Despite its rarity, ACC has a high propensity for local and metastatic relapses, occurring in nearly 75% of patients and contributing to an overall poor prognosis [3]. A population-based study in the Netherlands reported a 5-year survival rate of 32% for non-metastasized tumors, whereas patients with metastatic disease had an
abysmal 5% chance of surviving three years [4]. Similarly, an analysis using the USA SEER database found a 5-year cancer-specific survival rate of 38% [5].
ACC predominantly affects females, accounting for approximately 55% to 60% of cases [6, 7]. The disease fol- lows a bimodal age distribution, with incidence peaking in childhood and the fourth decade of life. Various oncogenic processes have been implicated in the molecular pathogen- esis of ACC. Mutations in tumor suppressor genes such as TP53, PRKAR1A, and MEN1 predispose individuals to ACC, along with other cancers [8]. Notably, one study observed that 27% of children and 3% of adults diagnosed with ACC had Li-Fraumeni syndrome, an autosomal-dominant inher- ited germline mutation in TP53 [9]. Additionally, the aber- rant activation of the Wnt/ß-catenin signaling pathway has been associated with ACC development
Due to the hormone-producing function of the adrenal cortex, ACC tumors can be classified as either functioning or non-functioning. Functioning tumors induce endocrine activity, whereas non-functioning tumors do not. Approxi- mately 40% to 60% of ACC cases are functional tumors [10, 11]. Hypercortisolism is the most frequent hormonal pres- entation, occurring in 50% to 80% of functional cases. The second most common is adrenal androgen secretion, which is observed in 40-60% of functional ACC cases, with about
☒ Yujiang Fang yujiang.fang@dmu.edu
1 Department of Microbiology, Immunology and Pathology, Des Moines University College of Osteopathic Medicine, West Des Moines, IA 50266, USA
2 Department of Surgery, University of Missouri School of Medicine, Columbia, MO 65212, USA
3 Ellis Fischel Cancer Center, University of Missouri School of Medicine, Columbia, MO 65212, USA
50% of functional tumors producing both cortisol and andro- gens [11]. The endocrine activity of functioning tumors can cause clinical symptoms such as Cushing’s syndrome, viri- lization, and, in rare cases, hypokalemia and hypertension due to aldosterone secretion [11, 12].
ACC is most often identified through hormonal hyper- secretion and tumor-related syndromes rather than as an incidental adrenal mass (adrenal incidentaloma) or parane- oplastic syndrome [13]. Unfortunately, large, randomized trials and advancements in treatment options have been hin- dered by the rarity of ACC. As a result, survival rates have remained largely unchanged for decades [14]. In this review, we will discuss current and potential future treatments for ACC that will hopefully improve outcomes in individuals with this rare disease.
Surgery
Surgical resection is the only potentially curative treatment and is recommended for any adrenal tumor suspected to be ACC. However, the 22% to 35% of patients that present with metastases at initial diagnosis should require a multi- disciplinary approach that considers initial systemic treat- ment. This may aid in stabilizing the tumor and preventing new lesions, thus allowing for resection [15]. Furthermore, ACC surgery should be performed by an expert in adrenal and oncological surgical principles to achieve an en bloc radical resection with an intact capsule for a microscopi- cally complete resection (R0 status). The resection may also need to include nearby tissue for locally advanced ACC [2, 16]. This is imperative to reduce the risk of loco-regional recurrence via capsule rupture in addition to the extreme care necessary to perform an anatomically deep surgery with adjacent hypervascularized regions [17]. Studies have shown that a complete surgical resection (R0) has the best chance for cure or tumor-free survival compared to incom- plete surgical resection. An overall survival (OS) of 32-48% at 5 years was achieved with R0 compared with a median survival of <1 year when there was a presence of residual disease [18]. This was further corroborated by a 2018 study that showed the 5-year OS for R0 at 48.8% compared to 22.6-28.6% for those with positive surgical resection mar- gins [19]. Therefore, the impact of microscopically negative surgical margins on OS has an utmost importance on surgi- cal approach.
Two common approaches to surgical resection are open adrenalectomy (OA) and minimally invasive adrenalectomy (MIA), which may include laparoscopic adrenalectomy (LA), robotic adrenalectomy, and retroperitoneoscopic adrenalectomy [20]. LA has been the favored approach for benign functioning and non-functioning adrenal dis- orders since its induction in 1992. Additionally, LA has
been proven to reduce surgical cost and complication rates while improving postoperative recovery [21]. Despite these benefits, initial studies showed patients undergoing LA for ACC to be at an increased risk of adverse outcomes. A ret- rospective cohort study from 2010 concluded that patients undergoing LA were at an increased risk of peritoneal car- cinomatosis compared to those undergoing OA [22]. The results of this study were supported by another retrospec- tive study on non-metastatic patients. This study found that the LA procedure resulted in the development of peritoneal carcinomatosis more frequently despite the resected tumors being smaller than those resected via OA. The study also concluded that OS and recurrence-free survival (RFS) were shorter for patients undergoing LA after pathologic T stage was adjusted [23].
However, some recent reports have suggested OA and MIA have comparable oncological outcomes [24]. A nation- wide analysis of patients who underwent resection found no significant difference in OS between MIA and OA, even in those with large (6-10 cm) and giant (> 10 cm) tumors [25]. An analysis of 11 studies found similar OS rates and recur- rence-free rates, with subsequent hazard ratios also being comparable. Interestingly, these rates were more favorable in OA at a 3-year mark which led to the conclusion that OA should remain the standard of care due to these trends. Overall, the differences in the results of these studies have been attributed to many factors: advancement in the tech- nical expertise of LA, surgeon experience with LA, selec- tion bias of smaller tumors for LA, and small sample sizes [21]. Unfortunately, the rarity of ACC has led to low-quality studies related to which surgical approach offers the best outcomes. As such, the European Society of Endocrinology (ESE) in collaboration with the European Network for the Study of Adrenal Tumors (ENSAT), and the American Asso- ciation of Endocrine Surgeons (AAES) have shared their recommendations. All agree that open surgery be conducted for confirmed or suspected ACC, although the experience of the surgeon is a defining factor [2, 16]. ESE/ENSAT addi- tionally adds that a LA approach is suggested for unilateral tumors suspicious of malignancy, have a diameter <6 cm and without evidence of local invasion [26]. However, the overall goal of surgical resection is to achieve R0 margins as stated earlier. Therefore, surgeons at high volume cent- ers that have extensive experience with these tumors, along with conducting more aggressive resection for fewer positive surgical margins, have the greatest ability to reduce recur- rence [27].
The significance of lymph node involvement has also been a topic of great importance on the OS of patients. A higher metastatic nodal burden has corresponded with worse OS while lymphadenectomy allowed for improved staging information. This is significant since N0-staged (no lymph node spread) patients have significantly better
survival compared to N1-staged (nearby lymph node spread) patients [28]. However, multiple previous studies proposed conflicting results on the role of lymphadenectomy in ACC which prompted a recent systematic review and meta-anal- ysis. The authors concluded that there may be an oncologi- cal benefit of lymphadenectomy in localized ACC (stage I-III) when undergoing curative surgery. Still, when patients with advanced and metastatic ACC were included in the analysis, lymphadenectomy had no impact on survival [29]. Fassnacht et al. provided a follow-up article that considered the previous review and their 60 years of collective clinical experience with managing patients with ACC. The authors recommended a minimum lymphadenectomy of the periad- renal and hilar nodes for all suspected cases of ACC [30]. As with the data acquired on OA and MIA surgeries, the conclusions that can be drawn from these studies are limited due to the reliance on retrospective studies, and therefore the extent of lymphadenectomy remains ambiguous.
Radiotherapy
Radiation therapy (RT) in an adjuvant role for ACC is controversial as the evidence supporting its use is limited and it has historically been considered radioresistant [31]. This may account for the small population of 9.5-11.7% of patients receiving RT despite studies suggesting its favorable use [32]. A retrospective analysis of 46 patients who under- went radical adrenalectomy with curative intent followed by postoperative adjuvant RT proposed a better 3-year OS and disease-free survival time in localized ACC, especially ENSAT I/II stage. However, this study is hindered by the lack of study participants and retrospective study limitations [33]. Another retrospective study concluded that adjuvant RT increases OS in non-metastatic ACC patients with high risk of recurrence. The high-risk factors included positive surgical margins, ≥ 6 cm tumor size, and high-grade disease [34]. Still, some authors evaluated the survival benefit of external adjuvant radiation therapy for patients with non- metastatic ACC who underwent R0 resection. The authors found no benefit of RT on OS in these patients even after subgroup analysis for National Comprehensive Cancer Net- work (NCCN) recommended guidelines [35].
RT in the advanced ACC setting is also of interest due to its palliative and possible therapeutic uses. Two studies have reported on the clinical benefit of RT [32, 36]. Kimpel et al. was the largest and assessed 132 tumoral lesions in 80 advanced ACC patients. It was found that RT produced a complete response (CR) in 6 tumoral lesions, partial response (PR) in 52, stable disease (SD) in 60, and progres- sive disease in 14. It was also concluded that a higher radia- tion dosage of> 50 Gy or stereotactic body RT resulted in significantly longer time to progression of the treated lesion
[36]. Although there were limitations to this study, this is an important starting point for warranting prospective stud- ies for the use of RT beyond just palliation. There is still a distinct lack of high-quality data informing guidelines for the use of RT in ACC. The current guidelines are against the use of RT in stage I-II and R0 resection although it may be considered with mitotane or on an individual basis in those with advanced ACC [2].
Chemotherapy
Mitotane is a drug originally derived from the insecticide DDT (Dichlorodiphenyltrichloroethane) and has been used since the 1970s for the treatment of adrenocortical carci- noma. It remains the only U.S. Food and Drug Administra- tion and the European Medicines Agency-approved adreno- lytic treatment for inoperable or metastatic ACC. While its exact mechanism of action is not fully understood, experi- mental research has previously suggested that mitotane works primarily by inhibiting adrenal steroidogenesis. It appears to alter steroid metabolism in peripheral tissues by producing metabolites that block key enzymes in the steroid synthesis pathway, particularly CYP11B1 (gene encoding 11ß-hydroxylase). This previous research concluded that reactive intermediates induced the necrosis of the adrenal zona fasciculata in mice following a CYP11B1-catalyzed reaction [37, 38]. However, expression of CYP11B1 iso- forms after mitotane treatment has conflicting data with downmodulation and upmodulation being observed depend- ing on the study [39]. Other experimental evidence has also suggested that CYP11B1 is an activator of mitotane but not necessary for mitotane-induced mitochondrial dysfunction. Additionally, mitotane has been identified to target transcrip- tional and functional CYP11A1 (gene encoding cholesterol- side chain cleaving enzyme), resulting in the accumulation of intramitochondrial free cholesterol [40]. Recent research has also shown mitochondria-associated membranes (MAM) to be a possible intracellular target of mitotane. Mitotane induces a decrease in aspartate with concomitant increase in glutamate via a time- and concentration-dependent manner. This could be linked to a mitotane-induced respiratory chain defect and subsequent cell apoptosis from reactive oxygen species [41]. Further in vitro studies have shown modulation of the ATF4 pathway, with significant upmodulation of the ATF3 gene, to be an early instigation by mitotane. Although the specific influence of this pathway on mitotane-induced cellular insult is not clearly understood, some of its effectors could someday be used for treatment monitoring or even new pharmacological targets [39].
Mitotane is broadly recommended as an adjuvant therapy for moderate- to high-risk ACC, particularly by the ESE [2], based on factors such as intraoperative spillage, vascular
invasion, or high-grade tumors. Terzolo et al. highlighted a significant therapeutic benefit of mitotane in the adjuvant setting, with a median OS of 110 months in the mitotane group compared to 52 and 67 months in control groups [42] (Fig. 1a). Wangberg et al. later reported a similar mitotane’s benefit that among patients with advanced-stage ACC, those with elevated mitotane levels had a markedly improved 5-year survival rate of 64.0%, compared to 28.6% in patients with lower levels [43] (Fig. 1b). However, the National Com- prehensive Cancer Network gives a weaker recommendation for adjuvant mitotane therapy following resection (category 3), referencing mixed evidence from retrospective studies [44]. Interestingly, Wangberg’s study also found that patients with stage II tumors exhibited very high 5-year survival rates (80.0-87.5%), regardless of mitotane levels [43].
ACC is characterized by a high recurrence rate, making RFS a critical focus in patient management. Evidence indi- cates that mitotane may delay recurrence. It was reported that hazard ratios for recurrence were 2.91 (95% CI 1.77-4.78;
P<0.001) and 1.97 (95% CI 1.21-3.20; P=0.005) for con- trol group 1 and 2, respectively, versus mitotane. Median RFS with mitotane was significantly longer at 42 months, compared to 10 and 25 months in the respective control groups [42] (Fig. 1a). These findings were confirmed in a follow-up study [45] and supported by another retrospec- tive analysis [46] showing that adjuvant mitotane therapy increases RFS. The ADIUVO trial (Adjuvant Mitotane ver- sus Surveillance in Low-Grade, Localized Adrenocortical Carcinoma) further revealed a better-than-anticipated prog- nosis, with a 5-year RFS of approximately 75% in patients with low-intermediate risk of ACC recurrence. However, the ADIUVO trial found no significant benefit of adjuvant mito- tane in low-risk ACC, resulting in recommendations against its routine use in this group [47]. The ongoing ADIUVO-2 trial, expected to report results in 2025, aims to address high-risk ACC but excludes a no-mitotane control arm. This omission limits its ability to definitively assess mitotane’s efficacy in the adjuvant setting.
a
b
120
90
100
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5-year survival rate
75
80
60
60
45
40
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20
15
0
0
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RFS
High mitotane Low mitotane Stage II (any mitotane)
Mitotane
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OS
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RFS of patients without second- line therapy
response
EDP-mitotane
Steptozocin-mitotane
EDP-mitotane
Steptozocin-mitotane
response, and disease control outcomes from the 304 ACC patients in the FIRM-ACT randomized clinical trial. Participants were assigned to receive either EDP-mitotane or streptozocin-mitotane. Objective response was defined as either a complete or partial response. Disease control was defined as a complete response, partial response, or stable disease, d median OS, PFS, and RFS (patients without second-line therapy) from the FIRM-ACT randomized clinical trial
Mitotane therapy is also often used in the advanced metastatic ACC setting. Evidence for single agent mitotane in advanced metastatic ACC is limited due to the rarity of ACC, with modest response rates associated with achiev- ing higher plasma levels (> 14 ug/mL). One study of 13 patients in the advanced/metastatic setting reported objec- tive responses in 4 (31%; 95% CI, 18-44%), including one complete radiographic response lasting 48 months and three hormonal responses ranging from 10 to 33 months. Higher mitotane plasma levels (> 14 µg/mL) were associated with better outcomes (P=0.02) [48]. Another study found an 11% response rate, with an 8% complete response [49]. A large French single-center retrospective study also suggested that mitotane treatment provided a survival advantage for patients with metastatic or residual ACC [50].
Combination therapies with mitotane have been explored in the metastatic setting, such as EDP (etoposide, doxoru- bicin, cisplatin) plus mitotane (EDP-mitotane) and strepto- zocin plus mitotane (streptozocin-mitotane) in the FIRM- ACT clinical trial. The EDP-mitotane group showed a higher objective response rate (ORR) (23.2% vs. 9.2%, P<0.001) and disease control rate (DCR) (58.3% vs. 31.4%, P<0.001) (Fig. 1c) while also having a longer median progression- free survival (PFS) (5.0 vs. 2.1 months, HR 0.55, 95% CI, 0.43-0.69, P<0.001) compared to streptozocin-mitotane. However, there was no significant difference in the over- all survival at 14.8 months for the EDP-mitotane group and 12.0 months for the streptozocin-mitotane group. Although OS was similar between the groups, the subset of patients who did not experience disease progression after first-line EDP-mitotane and did not receive alterna- tive second-line therapy had better OS with first-line EDP- mitotane (17.1 months) compared to streptozocin-mitotane (4.7 months) [51] (Fig. 1d). Small single-center single-arm studies on EDP-mitotane reported overall response rates of 53.5% [52] and 22% [53]. Importantly, response was recorded in both functioning and non-functioning tumors.
Although mitotane provides a therapeutic hope for patients with advanced or metastatic ACC, there are numer- ous adverse outcomes. The adverse outcomes of mitotane therapy consist of endocrinopathies and non-endocrinopathy adverse events (AE). Mitotane therapy can cause several endocrinopathies, including adrenal insufficiency, hypothy- roidism, and hypogonadism [54-60]. The mechanisms of endocrinopathies involve increased hepatic production of binding globulins and enhanced steroid metabolism due to the induction of CYP3A4 [54, 57]. Adrenal insufficiency occurs in all patients after a few months and requires supra- physiologic doses of glucocorticoids. Thyroid dysfunction, often secondary hypothyroidism, and hypogonadism, includ- ing gynecomastia and menstrual irregularities, are also observed. Patients may need higher doses of thyroid medi- cation and experience challenges in hormone replacement
due to mitotane’s effects on hormone-binding globulins and CYP3A4 activity. Regular monitoring and patient education on managing these conditions are essential, with particular attention to glucocorticoid management during stress or ill- ness [58, 60].
Mitotane-induced CYP3A4 activation is thought to reduce the efficacy of co-administered drugs, potentially explaining the need for increased warfarin doses [61] and heightened steroid requirements observed in patients receiv- ing mitotane therapy [62, 63]. The assessment of mitotane levels in advanced ACC treatment is also complicated by retrospective analyses, which are prone to biases due to the selection of groups comparable. Higher mitotane levels (≥ 14 µg/mL) are often achieved by healthier patients which potentially skews the outcomes [60]. The time to reach these levels (3-5 months) depends on the patients [64]. Those who remain fit enough to survive long enough to achieve thera- peutic levels may be favored in this aspect. The threshold of ≥ 14 µg/mL may be questionable, as the FIRM-ACT trial found no significant survival difference between patients with mitotane levels above or below this level [51] while a dedicated retrospective study found the opposite [65]. Addi- tionally, data on pediatric populations remain limited. More randomized controlled studies are needed to establish opti- mal therapeutic levels with meaningful clinical outcomes and reduced toxicity.
Mitotane therapy can also lead to several non-endocrine adverse events, requiring ongoing clinical and biochemi- cal monitoring [60]. Common side effects include gastro- intestinal (nausea, diarrhea, anorexia) and lipid disorders, which can often be managed by adjusting the dose or timing. Hepatic abnormalities, such as elevated transaminases and gamma-glutamyl transferase, occur in a significant portion of patients, though they generally resolve with dose reduction [66, 67]. Mitotane also stimulates hydroxymethylglutaryl- coenzyme A reductase which raises low-density lipoprotein levels in a majority of patients. Neurological symptoms like ataxia and confusion affect around 30% of patients but are usually reversible by adjusting the dose. Other less com- mon side effects include dyslipidemia, skin rash, and mild leukopenia [60].
Mitotane administration requires expertise due to its vari- able bioavailability and elimination, extensive tissue bind- ing, and lipid solubility. Its metabolism and pharmacokinet- ics could be influenced by physiological factors (e.g., lean body weight and sex) as well as genotypes [68, 69]. Dosage typically starts low and is gradually increased, with thera- peutic drug monitoring to optimize benefits and reduce toxic effects. High-fat meals improve absorption, and elimination continues long after stopping treatment [68].
The EDP-mitotane regimen has become a cornerstone of first-line treatment for advanced ACC based on the pivotal findings of the FIRM-ACT clinical trial. Despite its status
as the standard therapy for advanced ACC, other therapeutic approaches have been explored as second-line or salvage treatments.
The gemcitabine and 5-fluorouracil (5-FU) combination or capecitabine was evaluated in a phase II trial involving 28 advanced ACC patients who had progressed after the treat- ment by mitotane plus one or two systemic chemotherapies [70]. This therapy achieved a median PFS of 5.3 months and OS of 9.8 months, with 46.3% of patients remaining pro- gression-free after four months of treatment. A retrospective multicenter study of Gemcitabine-Based Chemotherapy par- tially corroborated these findings, reporting a median PFS of 12 weeks, a partial ORR of 4.9%, and a disease stabilization rate of 25.0% with a median duration of 26.8 weeks [71]. In contrast, a phase II study evaluating the combination of the multi-tyrosine kinase inhibitor sorafenib and weekly pacli- taxel as a second- or third-line treatment for 25 advanced ACC patients yielded poor results, leading to its exclusion as a recommended therapy [72].
Trofosfamide, an alkylating agent, was tested in a small cohort of 21 patients as a second- or third-line therapy. Although no objective responses were observed, the treat- ment achieved disease stabilization in 14% of patients, with a median PFS of 84 days and a median OS of 198 days [73]. Similarly, cyclophosphamide, another alkylating agent, showed disappointing response rates [74]. Thalidomide, once infamous for its teratogenic effects, has been repur- posed for its anti-angiogenic and immunomodulatory prop- erties. Trials of thalidomide treatment in ACC have resulted in DCR in only 2/27 (7.4%) patients and demonstrated no benefits [75].
Immunotherapy including monoclonal antibodies
With chemotherapy and mitotane being the only therapeu- tic options for advanced ACC [76], immunotherapies are of increasing interest in the treatment of advanced or metastatic adrenocortical carcinoma due to the demonstrated clinical benefits seen in many solid and hematologic malignancies. Tumors harness the critical mechanisms of immune check- point regulators such as programed cell death 1 (PD-1), pro- gramed death ligand 1 (PD-L1), and cytotoxic T lympho- cytes-associated protein 4 (CTLA-4) to escape the immune system [77]. A cohort study found that 26.5% of ACC tumor samples expressed PD-1, 24.7% expressed PD-L1, and 52.5% expressed CTLA-4. It was also observed that ACC tumors expressing CTLA-4 had a median of 38.4% posi- tive cells compared to tumors expressing PD-L and PD-L1, which had only 2.1% and 21.7% positive cells, respectively. Further analysis found that patients with PD-1 expressing tumors had a significantly better OS and PFS compared to
patients with tumors lacking this expression. Comparatively, PD-L1 and CTLA-4 expression in patients with ACC had no impact on OS and PFS [78].
To counteract cancer cells from evading the immune system, immune checkpoint inhibitors (ICIs) have been developed. Some of these ICIs include anti-CTLA-4, anti- PD-1, and anti-PD-L1 antibodies [79]. Of the previous immune checkpoint inhibitors, the drug pembrolizumab and nivolumab are anti-PD-1, avelumab is an anti-PD-L1, and ipilimumab is an anti-CTLA-4 (Fig. 2). Although these medications were initially approved for other cancers, their effects on ACC are of paramount importance. Multiple studies that are either ongoing, planned, or terminated have been looking at the efficacy of monotherapy pembrolizumab, monotherapy nivolumab, pembrolizumab in various com- binations, or nivolumab in combination with ipilimumab [80]. A paper by Ababneh et al. summarized the results of eleven unique studies for ORR, CR, PR, and SD rate. A majority of included studies assessed advanced/metastatic disease via 1 open-label phase I clinical trial, 6 open-label phase II clinical trials, 3 retrospective cohorts, and 1 case series. Of the 228 patients present throughout these stud- ies, 14-17% achieved the ORR with no significant differ- ence between monotherapy and combination therapy, 14% achieved PR, 29% achieved SD, and no patients achieved CR. Ten of the studies included the DCR which was found to be 42-52% with no significant difference between mono- therapy and combination therapy [81]. It is important to note that the Carneiro et al. nivolumab study reported 20% SD, 10% PR, and 70% progressive disease and was subsequently
Tumor cell
Avelumab
MHC
PD-L1
Pembrolizumab Nivolumab
Antigen- presenting cell
TCR
PD-1
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T-cell activation
terminated [82]. Additionally, avelumab therapy was found to have the lowest ORR at 6% even with almost half of study participants continuing mitotane treatment [83]. However, pembrolizumab monotherapy achieved a 14-23% ORR with- out concomitant mitotane treatment [84-86].
Additionally, ACC is characterized by the high expression of insulin-like growth factor 2 (IGF2), which has been shown to be overexpressed in up to 90% of ACC [87]. The effects of IGF2 are mediated by other highly expressed genes and their proteins that include insulin-like growth factor receptor 1 (IGF1R), insulin-like growth factor receptor 2, and insulin receptor isoform A [88]. Targeted therapies have focused on disrupting the IGF pathway. Cixutumumab (IMC-A12), a recombinant human IgG1 monoclonal antibody targeting IGF1R, was tested in combination with temsirolimus (inhibi- tor of mTOR, mammalian target of rapamycin) in 26 patients with metastatic ACC. This combination achieved disease stabilization for over six months in 42% of patients [89]. However, a subsequent multicenter randomized double-arm phase II trial comparing Cixutumumab plus mitotane to mitotane alone was terminated early due to limited efficacy and slow accrual [90]. Linsitinib, another IGF1R inhibitor, was evaluated in a large clinical trial involving 139 patients with locally advanced or metastatic ACC. Unfortunately, it failed to improve PFS or OS compared to placebo [9185].
Although immunotherapies are commonly tolerated, there is a risk of adverse events. It was found that 59% of patients receiving pembrolizumab without mitotane continuation had some AE and 13% had grade III/IV. Of the AEs, elevated liver enzymes was the most common laboratory finding while fatigue was the most common general disorder [861]. Patients receiving avelumab without mitotane continuation had an 80% chance of AE although a lower chance of 8% of the AE being grade III or higher [83]. As a likely expecta- tion, patients continuing mitotane therapy had a greater over- all risk of AE than patients not receiving mitotane [83, 92].
Future direction
ACC is a rare and deadly disease that aggressively attacks one’s body, resulting in a dismal 5-year survival. A stagnant therapy regimen for decades has failed to improve the out- comes of patients unfortunate enough to present with this disease. Surgery continues to remain the only curative option for ACC and there is still incomplete data on the efficacy and mechanistic action of the primary adjuvant therapy, mito- tane. The growing use of immunotherapy and the accumulat- ing data is a step in the right direction. Table 1 summarizes the current clinical studies investigating immunotherapies in ACC. However, there may still be other options that remain under investigation or are not yet fully understood. Trabectedin is a new marine-derived agent being tested
for its antitumor effects in ACC cells. Preliminary results have shown its cytotoxic ability and interference with inva- siveness and metastatic processes [93]. APOC1 and APOE have also been discussed as possible prognostic markers or pharmaceutical targets. Patients with ACC that had lower expression of these genes had longer OS and disease-free survival times than those with high expression. Molecular studies have proposed that these genes have a plethora of functions involved in cancer development and progression [94]. Maternal embryonic leucine zipper kinase (MELK) and cyclin-dependent kinase (CDK) inhibitors have gained the interest of researchers. Ribociclib is a CDK4/6-inhibitor that exerts its action by interfering in cell-cycle progression. Early data show its efficacy in reducing cell proliferation and its cytotoxicity to ACC cell lines in vitro. Addition- ally, there was a positive reaction on cell viability when ribociclib was combined with progesterone and/or mitotane [95]. A recent study found that a synergistic combination of MELK and CDK inhibitors affected downstream molecules of the Wnt/B-catenin signaling pathway and cell-cycle arrest in vitro. Additional in vivo data suggested a meaningfully lower tumor burden in mouse models [96].
Furthermore, chimeric antigen receptor T-cell therapy (CAR-T) is an immunotherapy that modifies a patient’s own T-cells to more effectively target and eliminate cancer cells. This has been approved for blood cancers including B-cell precursor acute lymphoblastic leukemia and diffuse large B-cell lymphoma and may represent an avenue for ACC therapy considering its effectiveness in these cancers. However, there is very little research on CAR-T use in ACC except for data supporting a focus on targeting interleu- kin-13 receptor subunit alpha-2. This interleukin is over- expressed in ACC and other cancers and has been shown to promote various tumor pathogenesis [97]. Despite a current lack of data supporting CAR-T use in ACC, this therapy may represent a viable treatment for ACC in the future as research progresses.
The use of peptide receptor radionuclide therapy (PRRT), a type of endoradiotherapy, has been established for various neuroendocrine tumors such as well-differentiated midgut tumors [98]. This treatment uses a radiolabeled peptide to deliver cytotoxic radiation directly to tumor cells through specific binding to a molecular target [99]. Therefore, PRRT can be used to individualize treatment based on the predomi- nant molecular targets expressed in ACC tumor cells. Tar- gets such as somatostatin receptor, prostate-specific mem- brane antigen, and C-X-C motif chemokine receptor 4 have been investigated, showing overexpression in ACC tumor cells depending on the case. However, there is a lack of data surrounding the use of PRRT against these targets and there- fore highlights an area for further research. In contrast, the enzymes CYP11B1 and CYP11B2, which were discussed earlier, are the most promising targets to date. Patients that
| Drug | Population | Primary outcome measure | Clinical trials.Gov identifier | Study phase | Status |
|---|---|---|---|---|---|
| Pembrolizumab | Adults (≥18 years of age) with confirmed unresectable or meta- static ACC | ORR RECIST 1.1 through about 2 years of the study | NCT02673333 [70] | II Active | |
| Pembrolizumab | Adults with various non- resectable or metastatic rare tumors | Non-progression rate at 27 weeks assessed by irRECIST | NCT02721732 | II Active | |
| Pembrolizumab + rela- corilant | Adults with confirmed unresectable or metastatic ACC and glucocorticoid excess | Dose-limiting toxicity through up to 12 weeks | NCT04373265 | Ib Completed | |
| Pembrolizumab + len- vatinib | Adults (≥19 years of age) with ACC follow- ing failure of chemo- therapy (platinum- and mitotane-based) | Anti-tumor activity of drug combination through study comple- tion | NCT05036434 | II Enrolling by invitation | |
| Pembrolizumab + cabo- zantinib | Adults (≥18 years of age) with confirmed unresectable or meta- static ACC | ORR RECIST 1.1 | NCT06006013 | II Active | |
| Pembrolizumab | Adults after first-line EDP or EDP-mitotane | ORR through about 4 years of the study | NCT05563467 | II Recruiting | |
| Mitotane + pembroli- zumab | Adults with confirmed ACC | ORR RECIST 1.1 through about 1 year of the study | NCT05634577 | II Completed | |
| Ablative radiother- apy + pembrolizumab | ≥ 15 years of age with confirmed ACC and liver metastases | Evaluating safety of treatment based on AE | NCT06066333 | II Recruiting | |
| Nivolumab + ipilimumab | Adults with unresectable or metastatic genitouri- nary tumors | ORR RECIST 1.1 through up to 2 years | NCT03333616 | II Active | |
| Nivolumab + ipilimumab | Adults with various rare tumors | ORR RECIST 1.1 through up to 10 years | NCT02834013 | II Active | |
were treated with the radiopharmaceutical [13]]]IMTO, a CYP11B1/2 inhibitor, had a median PFS of 14 months, with 5 patients showing stable disease and 1 showing partial response [98]. There is a plethora of therapeutic options on the horizon for patients with ACC. Continued research into these new therapeutic options is essential for the well-being and survival of current and future ACC patients.
Acknowledgements This study was supported by a grant from Des Moines University for Dr. Yujiang Fang (IOER 112-3119). Figure 2 was created with BioRender.com
Author contributions D.M.S .: writing-original draft, and writing- review and editing. E.X.J: writing-original draft, and writing-review and editing. T.G.M .: writing-review and editing. B.C.C .: writing- review and editing. M.R.W .: writing-review and editing. Y.F .: con- ceptualization, and writing-review and editing. All authors have read and agreed to the published version of the manuscript.
Data availability No datasets were generated or analyzed during the current study.
Declarations
Conflict of interest The authors declare no competing interests.
Use of AI tools declaration The authors declare they have not used Artificial Intelligence (AI) tools in the creation of this article.
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