The Adrenal Gland as a Sanctuary Site of Metastases After Pembrolizumab Treatment: A Case Series

Nguyen, Michelle C.; Shah, Manisha H.; Liebner, David A.; Backes, Floor J.; Phay, John E.; Shirley, Lawrence A.

doi:10.6004/jnccn.2018.7059

Cited by 19 publications

(25 citation statements)

References 23 publications

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“…Few clinical case reports of ICI-treated solid tumors and surgical series of patients with melanoma suggest that adrenal glands might be a sanctuary for tumor cells. 7 No warning signal has been reported for patients with lung cancer, though. 3 Our case series with five tumor progressions limited to the adrenal glands in patients with MSI/ dMMR mCRC is striking since CRC involving adrenal glands is uncommon.…”

Section: Discussionmentioning

confidence: 99%

Adrenal gland as a sanctuary site for immunotherapy in patients with microsatellite instability-high metastatic colorectal cancer

Cohen

Jonchère

Fouchardière

et al. 2021

J Immunother Cancer

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Metastatic colorectal cancers (mCRC) harboring microsatellite instability (MSI) are sensitive to immune checkpoint inhibitors (ICIs), but the mechanisms of resistance to ICIs remain unclear. Dissociated responses in patients with ICI-treated cancer suggest that certain organs may serve as sanctuary sites due to the tumor microenvironment. This case series describes five patients with ICI-treated MSI mCRC with disease progression limited to the adrenal glands. At ICI initiation, three patients were free of metastasis in the adrenal glands. Four patients experienced objective response per RECIST (Response Evaluation Criteria in Solid Tumors) while treated with ICI. ICI treatment was discontinued due to progressive disease limited to the adrenal glands (n=3) or toxicity (n=2). The time between ICI initiation and progression in the adrenal glands ranged from 11 to 39 months. Adrenalectomy (n=3) and stereotactic body radiation therapy (n=2) were performed. At the last follow-up, all patients were alive and progression free. Molecular analyses were performed in one patient. A significant impairment of the antigen presentation pathway was observed in the ICI-resistant lesion of the adrenal gland, which could be explained by the presence of glucocorticoids in the adrenal gland microenvironment. We also detected an overexpression of TSC22D3, a glucocorticoid-target gene that functions as a mediator of anti-inflammation and immunosuppression. This case series suggests that the adrenal glands may be the sanctuary sites for ICI-treated MSI mCRC through the glucocorticoid-induced impairment of the antigen presentation machinery.

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Section: Discussionmentioning

confidence: 99%

Adrenal gland as a sanctuary site for immunotherapy in patients with microsatellite instability-high metastatic colorectal cancer

Cohen

Jonchère

Fouchardière

et al. 2021

J Immunother Cancer

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“…Taken together, these findings suggest that the tissue-specific tumor microenvironment differs between various metastatic sites and between patients. [8][9][10] In line with these findings, Nguyen et al 11 reported a case series of 3 patients with progression of adrenal gland metastases (AGMs) despite objective responses to the anti-PD-1 therapy pembrolizumab in all other metastatic sites. This supports the hypothesis that certain tissues in the body may possess tissuespecific resistance mechanisms because of different tumor microenvironments.…”

Section: Introductionmentioning

confidence: 82%

“…However, as previous case reports and studies have shown, AGMs may present an obstacle for successful treatment of patients with advanced-stage disease. 11,18,23,24 We and others have hypothesized that the adrenal gland may serve as a so-called sanctuary site, as defined by their inherent immunosuppressive microenvironment, allowing the tumor to grow in an immunologically permissive milieu and limiting the efficacy of ICIs. To further investigate this, we performed a large, single-center, retrospective analysis of all patients with stage IV melanoma with and without an AGM who were treated with ICIs.…”

Section: Discussionmentioning

confidence: 99%

“…Differences in site-specific ICI responses have been observed in other cancers, such as in lung cancer, where metastases to the adrenal gland have also been shown to be more resistant to anti-PD-1 therapy. 11 Likewise, when considering primary tumors of the adrenal gland, treatment with immunotherapies has similar disappointing results. 39 Cosentini et al 39 proposed an interesting model to explain how tumor intrinsic and systemic factors could impair immunotherapy efficacy in adrenocortical carcinoma (ACC).…”

Section: Discussionmentioning

confidence: 99%

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Melanoma Metastases to the Adrenal Gland Are Highly Resistant to Immune Checkpoint Inhibitors

Borgers

Tobin

Torphy

et al. 2021

Journal of the National Comprehensive Cancer Network

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Background: Adrenal gland metastases (AGMs) are common in advanced-stage melanoma, occurring in up to 50% of patients. The introduction of immune checkpoint inhibitors (ICIs) has markedly altered the outcome of patients with melanoma. However, despite significant successes, anecdotal evidence has suggested that treatment responses in AGMs are significantly lower than in other metastatic sites. We sought to investigate whether having an AGM is associated with altered outcomes and whether ICI responses are dampened in the adrenal glands. Patients and Methods: We retrospectively compared ICI responses and overall survival (OS) in 68 patients with melanoma who were diagnosed with an AGM and a control group of 100 patients without AGMs at a single institution. Response was determined using RECIST 1.1. OS was calculated from time of ICI initiation, anti–PD-1 initiation, initial melanoma diagnosis, and stage IV disease diagnosis. Tumor-infiltrating immune cells were characterized in 9 resected AGMs using immunohistochemical analysis. Results: Response rates of AGMs were significantly lower compared with other metastatic sites in patients with AGMs (16% vs 22%) and compared with those without AGMs (55%). Patients with AGMs also had significantly lower median OS compared with those without AGMs (3.1 years vs not reached, respectively). We further observed that despite this, AGMs exhibited high levels of tumor-infiltrating immune cells. Conclusions: In this cohort of patients with melanoma, those diagnosed with an AGM had lower ICI response rates and OS. These results suggest that tissue-specific microenvironments of AGMs present unique challenges that may require novel, adrenal gland–directed therapies or surgical resection.

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“…No systemic therapy was utilized in those cases ( 14 ). A recently reported series consisted of two melanoma cases, and one uterine carcinosarcoma case, presenting with adrenal residual metastasis after pembrolizumab ( 15 ). Local therapy was effective in treating adrenal lesions in these cases.…”

Section: Discussionmentioning

confidence: 99%

Adrenal Metastases as Sanctuary Sites in Advanced Renal Cancer

Vaishampayan

Shah

Asad

et al. 2020

jkcvhl

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Involvement of the adrenal gland in kidney cancer represents a unique site of metastasis with a distinct clinical course. The cases are typically resistant to immune therapy and need local therapy management. A case series of patients with adrenal metastases was reviewed to highlight the nuances of clinical course and therapy. We reviewed renal cancer carcinoma (RCC) cases with adrenal metastases at Karmanos Cancer Center, Detroit MI. Medical records were reviewed to collect relevant case information. Next-generation sequencing, tumor mutation burden testing, and programmed death ligand biomarkers were evaluated in five cases. Twelve cases were reviewed; all were males with a median age of 49.5 years. Three patients presented with adrenal metastases only and were treated with local therapy. Three received interleukin-2 (IL-2). One patient relapsed with bilateral adrenal lesions after 11 years of remission, post-IL-2 therapy. Five cases received immune checkpoint inhibitor (ICI) and one received antivascular therapy. ICI therapy was followed by ablation of residual adrenal metastases in three patients. Genomic profiling was available in five cases. All were BAP1 and PD-L1 negative. Pathogenic mutations in PBRM1, SETD2, and VHL were noted. All patients with residual adrenal metastases responded to antivascular therapies or to local ablation. One patient died 17 years after diagnosis and 11 patients are alive at a median follow-up of 9.5 years. Adrenal metastases in RCC have a distinct clinical course. They can represent a sanctuary site of relapse/residual disease following treatment with immune therapy. Management with local therapy can induce durable remissions. Systemic management with antivascular therapies also demonstrated favorable responses. Further investigation should focus on the unique clinical course and optimal management of adrenal metastases in kidney cancer.

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The Adrenal Gland as a Sanctuary Site of Metastases After Pembrolizumab Treatment: A Case Series

Cited by 19 publications

References 23 publications

Adrenal gland as a sanctuary site for immunotherapy in patients with microsatellite instability-high metastatic colorectal cancer

Adrenal gland as a sanctuary site for immunotherapy in patients with microsatellite instability-high metastatic colorectal cancer

Melanoma Metastases to the Adrenal Gland Are Highly Resistant to Immune Checkpoint Inhibitors

Adrenal Metastases as Sanctuary Sites in Advanced Renal Cancer

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