Oncologist ®
Metastatic Adrenal Cortical Carcinoma Responding to Octreotide: A Case Report
XIANG WANG,ª NA ZHOU,ª YU XIAO, WENJIA ZHU,” CHUNMEI BAI,ª LIN ZHAOª
Departments of ªMedical Oncology and Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; “Departments of Nuclear Medicine and Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China
Disclosures of potential conflicts of interest may be found at the end of this article.
ABSTRACT
Advanced adrenocortical carcinoma (ACC) is an aggressive disease with poor prognosis, and the current therapeutic options, such as mitotane or platinum-based chemother- apy regimens, often offer limited efficacy. Here, we present the first report, to the author’s knowledge, of metastatic ACC with positive octreoscan scintigraphy that was successfully treated with octreotide long-acting release (LAR). A patient with metastatic ACC who showed poor tolerance to mitotane received octreotide LAR because of positive octreoscan
scintigraphy. She obtained major partial response to the somatostatin analog. Interestingly, the expression of somatostatin receptor 2 from the previous local recurrence lesion was negative. The next-generation sequencing-based circulating tumor DNA analysis in the patient was per- formed and failed to identify any alterations. These findings suggest that octreotide LAR may be a good option for the treatment of metastatic ACC in selected patients. The Oncologist 2019;24:e793-e797
INTRODUCTION
Adrenocortical carcinoma (ACC) is a rare, heterogeneous malignancy with a dismal prognosis [1]. Completed surgical resection is the only potentially curative treatment for ACC. In advanced ACC, medical therapies, such as mitotane or platinum-based chemotherapy regimens, offer limited effi- cacy [2-4]. As the majority of the patients experience a rapid and inexorable progression, new therapies for advanced ACC are urgently needed. We describe a case of metastatic ACC with positive octreoscan scintigraphy that was successfully treated with octreotide long-acting release (LAR).
CASE PRESENTATION
A 45-year-old woman was admitted to Peking Union Medical College Hospital in December 2009 because of a left abdomen mass incidentally discovered by abdominal ultrasonography. Abdominal computed tomography (CT) scan confirmed a 7.1 x 6.0 cm heterogeneous mass in the left adrenal. She had no clinical symptoms associated with steroid excess. Her previous medical history and her family history were unremarkable. Her blood pressure was 110/70 mmHg. Hormone testing revealed normal serum cortisol but elevated urine-free cortisol of 275.2-293.9 µg per 24 hours (normal 12.3-103.5). The somatostatin receptor imaging with 99Tc™-hydrazinon-icotinyl-
Tyr3-octreotide was negative (Fig. 1A). The patient underwent surgical removal of the left adrenal tumor on December 28, 2009. The histopathologic diagnosis was an adrenal cortical cortex adenoma. Immunohistochemistry (IHC) was as follows: melan-A (+), Vim (+), a-inhibin (-), S-100 (-), Syn (-), AE1/AE3 (-), and Ki67 (index 3%). After the operation, the urine-free cortisol level normalized and the patient was followed up regularly.
The patient remained disease-free until February 2012, when CT scan revealed multiple nodules in the left fatty renal capsule. Fluorodeoxyglucose-fused positron emission tomog- raphy with CT (FDG-PET-CT) confirmed the presence of the nodules and also revealed a metastasis retroperitoneal lymph node. Laboratory tests, including a hormonal study, were nor- mal at that time. The radical left nephrectomy plus retroperi- toneal lymphadenectomy was subsequently performed on March 5, 2012. The histopathological examination demon- strated recurrent adrenocortical adenoma, potentially malig- nant, with a Weiss score of 2/9, including the mitotic rate being 38 per 50 high-power fields and invasion of the cap- sule, with IHC as follows: «-inhibin (-), calretinin (±), melan- A (+), CgA (-), Syn (+), p53 wild type, S-100 (-), AE1/AE3 (-), Ki67 (index 10%; Fig. 2). The patient received radiotherapy to the tumor bed, to a total dose of 50.4 Gy, 1.8 Gy per fraction
Correspondence: Lin Zhao, M.D., Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No. 41 Damucang hutong, Xicheng District, Beijing 100032, People’s Republic of China. Telephone: +86-10-69158770; e-mail: wz20010727@aliyun. com Received December 4, 2018; accepted for publication April 10, 2019; published Online First on May 9, 2019. http://dx.doi.org/ 10.1634/theoncologist.2018-0855
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per day, up to 28 fractions in total, in order to reduce recur- rence from May to June 2012.
The patient had an uneventful postoperative period with- out any adjuvant therapy. The follow-up thoracic and abdomi- nal CT scans were unremarkable until April 2017. The CT scan showed multiple metastasis lung nodules and intraperitoneal lesions, which were also identified on FDG-PET-CT (Fig. 1B). The somatostatin receptor imaging with 99Tc™-hydrazinon- icotinyl-Tyr3-octreotide was positive (Fig. 1C). Hormone testing revealed normal serum cortisol but elevated urine- free cortisol of 119.9 µg per 24 hours. Considering the patient’s medical history and the results of examinations, metastatic adrenocortical carcinoma was diagnosed. The patient refused to receive needle biopsy for further histo- pathological assessment. Therefore, she administered initially on 1.5 g per day of mitotane as monotherapy from August 7, 2017, with dose increments up to 3 g daily after 2 weeks. She suffered grade 3 fatigue, nausea, and vomiting during therapy, which could not be relieved by reduced or inter- rupted dose. Thus, she was required to stop mitotane treatment after October 9, 2017. Owing to fear of the che- motherapeutic toxicity, the patient refused to receive che- motherapy. Therefore, she had not received any treatment during the next 2 months.
Because of the positive octreoscan scintigraphy, the patient administered on octreotide LAR 20 mg per month from December 13, 2017. She tolerated treatment well
without any side effects. After 15 months of treatment, she had gained 10 kg, and CT scan (Fig. 3B) showed major partial response, which was a marked improvement from the CT scan before the initiation of therapy (Fig. 3A). Also, the level of urine-free cortisol normalized after 6 months of treatment. As of the publication date, the patient is asymptomatic and con- tinues to take octreotide LAR 20 mg monthly. To find out the reason of the dramatic results, we examined the expression of somatostatin (SST) receptor (SSTR) 2 by IHC with the sec- ond surgical formalin-fixed paraffin-embedded specimens. However, the expression of SSTR2 was negative (Fig. 2). Next- generation sequencing-based circulating tumor DNA (ctDNA) analysis of 1,021 genes was applied to peripheral blood sam- ples to detect point mutations, copy number alterations, insertion and deletion mutations, and all known fusion genes alterations after 6 months of treatment for a sequencing depth of 1000x. The reliability of the ctDNA assay applied in this study has been assessed in several studies [5-7]. The gene profiling also failed to identify any somatic or germline mutations.
DISCUSSION
Treatment of metastatic ACC poses a significant challenge because of limited therapies. Over the last few years, despite the remarkable improvement in our understanding of molecu- lar pathogenesis in ACC, there has been no significant change
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in treatment options yet. Mitotane and platinum-based che- motherapy are still the gold standard in metastatic ACC despite suboptimal efficacy [2-4]. In a multicenter cohort study, the objective response rate with mitotane mon- otherapy was only 20.5%, the median progression-free sur- vival (PFS) was 4.1 months, and median overall survival (OS) was 18.5 months [3]. The largest trial of advanced ACC
to date, the FIRM-ACT trial, described an objective response rate of 23%, median PFS of 5.0 months, and median OS of 14.8 months with mitotane plus a combination of etoposide, doxorubicin, and cisplatin [4]. Tyrosine kinase inhibitor use such as insulin-like growth factor type-1 (IGF-1) receptor [8, 9], vascular endothelial growth factor receptor [10-12], and epidermal growth factor receptor [13] did not result in
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meaningful benefit in patients with ACC. Multiple ongoing clinical trials are currently evaluating the role of immune checkpoint inhibitors (ICIs) in ACC (ClinicalTrials.gov Identi- fier: NCT033333616, NCT02834014, NCT02673333, and NCT02721732). However, the efficacy and safety of ICI treat- ment is still unclear.
To the best of our knowledge, this is the first case of ACC treatment with octreotide LAR leading to marked tumor shrinkage. The discovery of SST and the identification of sta- ble SST analogs with a longer half-life have raised new hopes for the treatment of endocrine tumors. SST takes effect through five SSTRs and is a hormone peptide that has anti- secretory effects on various endocrine and neuroendocrine cells; it also has an antitumor activity and antiproliferative properties, which has been shown in in vitro studies [14, 15] and randomized, controlled trials such as PROMID and CLAR- INET studies [16, 17]. PROMID showed that octreotide LAR significantly lengthened PFS compared with placebo in mid- gut gastroenteropancreatic neuroendocrine tumors (NETs) (14.3 vs. 6 months). CLARINET also showed a significantly prolonged PFS with lanreotide as compared with placebo in grade 1 or 2 NETs (median not reached vs. 18.0 months). The possible mechanisms included mediating MAPK extracel- lular signal-regulated kinase pathway and inhibition of the release of growth factors and hormones, such as insulin, pro- lactin, IGF-1, gastrin, that drive tumor growth and so on [11]. A recent study also showed that octreotide decreases PI3K/Akt pathway activity in pituitary and pancreatic adeno- carcinoma cell lines [18].
Previously, SSTR subtypes have been identified in ACC [19-21], although the IHC of SSTR2 in our patient was nega- tive. According to Unger et al.’s report [19], using immunohis- tochemistry, SSTR2, 3, and 4 were found in 3-4 (12%-16%) out of 25 ACCs, and SSTR5 was detected in six (24%) of the samples. None of the ACCs expressed SSTR1. The majority of positively stained adrenal carcinoma revealed a positive staining in <30% of tumor cells. In contrast, according to Mar- iniello et al.’s data [20], SSTRs were abundantly expressed in ACC. They found that SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5 expressed 84.6%, 100%, 69.2%, 38.5%, and 84.6%, respec- tively, in 13 ACCs by real-time polymerase chain reaction. Immunohistochemistry confirmed the mRNA expression data. Germano et al. [21] also demonstrated that ACC expressed all SSTRs. SSTRs were variably expressed in 29% (SSTR2) up to 83% (SSTR4) of 58 cases of AAC, with a membrane or cytoplasmic reactivity. Jing et al. [22] once used somato- statin receptor imaging with 99Tc™-hydrazinon-icotinyl- Tyr3-octreotide in 327 patients with documented adrenal lesions. Increased uptake was observed in three cases of ACC (they did not describe the positive rate of octreoscan). Therefore, it is noteworthy that a potential therapeutic role for SST analogs could be used in ACC. In a previous case report [23], the authors explained that treating a secret- ing ACC with octreotide led to marked symptom relief and a drop in corticosteroid secretion despite the negative octreoscan. But they did not report whether the tumor shrunk or not. However, until now, there has not been any study to explore the antitumor activity of SST ana- logs in adrenocortical tumors.
Octreotide is an SST analog which bind with high affinity to SSTR2 and to a lesser extent with SSTR3 and SSTR5 [24]. In our patient, there was a dramatic response to octreotide despite the negative SSTR2 of IHC analysis. This result was likely related to the following reasons: first, the expression of SSTR2 originating from the second surgical samples may not represent the current situation because the expression of SSTR is not always similar between metastatic lesions and primary tumor [25]. Likewise, it is maybe the reason why the results of octreoscan were different between the initial stage and the present stage. Second, the expression of other SSTRs was unknown due to no corresponding anti- bodies, so octreotide may play an antitumor activity by means of binding with SSTR3 or SSTR5. Third, there were discrepancies between SSTR IHC and somatostatin receptor scintigraphy (SRS) findings. Previous studies have evaluated the concordance between IHC and SRS results in neuroen- docrine neoplasms [26-30]. The correlation of the SSTR2 and SRS findings varied by 64%-92.9%. Moreover, Diakatou et al. [30] found that the results of SRS were positive in 4 of 81 (4.9%) patients, whereas the IHC were negative.
Genomic characterization of adrenocortical carcinoma has been recently established, leading to the identification of specific molecular patterns of adrenocortical carcinoma associated with clinical outcome [31-34]. Among these, a specific gene expression pattern (i.e., high BUB1B-PINK1 levels [31, 32]), specific copy number alteration [33], and CpG islands methylation patterns [32, 34] have been associated with a poor prognosis. A recent study also proposed a combi- nation of molecular, clinical, and histopathological param- eters, including number of somatic mutations, alterations in Wnt/B-catenin and p53 pathways, promoter regions meth- ylation pattern, tumor stage, grading, resection status, age, symptoms caused by steroid autonomous secretion, or tumor mass to improve prognostication, in patients with advanced ACC. However, the authors found that none of the single molecular events showed a significant predictive role for response to mitotane monotherapy, etoposide-doxoru- bicin-cisplatin, gemcitabine plus capecitabine, and/or streptozotocin [35]. Our next-generation sequencing-based ctDNA also failed to identify any mutations because no circu- lating tumor DNA was detected. It is noteworthy, however, that there has not been any molecular marker showing a pre- dictive role for response to octreotide until now.
CONCLUSION
Patients with advanced ACC have a poor overall prognosis. The patient with metastatic ACC in this article showed excep- tional response after initiation of octreotide LAR. To our knowledge, this is the first case of metastatic ACC with positive octreoscan scintigraphy successfully treated with octreotide LAR. In view of the limited efficacy of current agents in ACC, a trial of octreotide LAR may be a good option for patients of metastatic ACC with positive octreoscan.
DISCLOSURES
The authors indicated no financial relationships.
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