Seminars in Oncology xxx (xxxx) xxx
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Seminars in Oncology
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Seminars in
Oncology
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Me-Too Therapies in Cancer, Part 1
Letter to Editor: Reply to R.T. Casey (Semin Oncol. 2018 Jun;45(3):151-155)
Impressive response to anti PD-1 immunotherapy in a patient with adrenocortical carcinoma with mismatch-repair deficiency and low cortisol levels
Adrenocortical carcinoma (ACC) is a rare endocrine tumor with 50% of newly diagnosed patients having unresectable or metastatic disease. In patients with advanced ACC, adrenal tumor resection and treatment with mitotane plus chemotherapy is recommended. Despite these treatments, the prognosis of these patients remains poor. In the immunotherapy era, efforts are being made to ex- tend this treatment to all cancers but it is necessary to select pa- tients who can benefit from immunotherapeutic treatment. It was demonstrated that mismatch repair deficient (MMRd) tumors are more responsive to anti-PD-1 antibody pembrolizumab. The im- pact of steroid exposure on immunotherapy efficacy is unclear, al- though high levels of steroids may reduce immunotherapy out- come; on the other hand, in this “Letter to Editor”, in reply to R.T. Casey (Semin Oncol. 2018 Jun;45(3):151-155), we report, for the first time, a case of a remarkable response to pembrolizumab in a patient with metastatic MMRd adrenocortical carcinoma and low cortisol levels in the blood.
We read with interest the manuscript by Casey and colleagues [1] who reported a case of rapid disease progression in a patient with mismatch repair-deficient (MMRd) and cortisol secreting adrenocortical carcinoma (ACC) treated with pembrolizumab. On the contrary, we have come across a similar case of MMRd advanced ACC but with low cortisol levels who achieved a documented response to pembrolizumab. A 29-year-old man presented with fever and abdominal pain. A CT scan revealed a left adrenal mass and multiple bilateral lung nodules. The study of adrenal secretion revealed increased testosterone levels and ACTH-independent hypercortisolism. He underwent adrenalectomy with confirmed diagnosis of an ACC. Biopsy of the pulmonary nod- ules confirmed the diagnosis of metastatic ACC. The patient began treatment with mitotane and received doxorubicin, etoposide and cisplatin as first-line therapy, followed by gemcitabine plus capecitabine in second line. After 6 cycles of both chemotherapy treatments, CT scan revealed progression of his lung metastases. Analysis of his tumor for the mismatch repair complex by im- munohistochemistry showed no expression of MSH2 and MSH6; PD-L1 expression was 1%. Lynch-syndrome was excluded. The patient was begun on pembrolizumab (200 mg flat-dose Q3w) and maintained on mitotane therapy. On mitotane his urinary free cortisol levels before starting pembrolizumab were normal (77 nmol/24-hour; normal range: 16-168). After the first pem- brolizumab infusion, liver toxicity occurred with grade 4 elevations of serum transaminases and hyperbilirubinemia with serology for
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hepatitis viruses negative. Consequently pembrolizumab was discontinued and liver toxicity was managed with corticosteroid therapy until complete resolution 12 weeks later. Mitotane was also administered and cortisol levels remained in the normal range throughout therapy. Therapy with methylprednisone was discontinued and 3 months after starting pembrolizumab, a CT showed a partial response according to RECIST Criteria [2] (see Fig. 1). Treatment with pembrolizumab was resumed and thera- peutic steroid doses were discontinued. To date, after 6 months, pembrolizumab therapy continues, and a recent CT scan demon- strated further shrinking of all lesions. Regarding immunotherapy efficacy, mismatch repair deficiency has been reported to be
[mUS5Gb;January 11, 2019;20:26]
M. Caccese, F. Ceccato and M. Fassan et al./Seminars in Oncology xxx (xxxx) xxx
associated with responsiveness to anti-PD-1 therapy in several cancers [3] and can be detected using immunohistochemistry. To the best of our knowledge, we described for the first time, a case of metastatic MMRd ACC with mitotane-induced suppression of cortisol secretion treated with an immune checkpoint-inhibitor. In the patient described by Casey and colleagues, high cortisol levels due to the discontinuation of mitotane during pembrolizumab treatment may have been the cause of rapid disease progres- sion and no response to immunotherapy. Additionally, in our patient, pembrolizumab was administered after receiving prior chemotherapy treatments and this could have led to an increase in tumor mutation load, making it more responsive to the immune checkpoint-inhibitor treatment [4-6]. Despite hepatitis being a rare immune-related adverse event associated with pembrolizumab, it was reported in both patients, which could be due to the asso- ciation of mitotane, a hepatotoxic agent, although, in our patient, mitotane was not discontinued and liver toxicity resolved with corticosteroids alone. We concluded that immune checkpoint- inhibitors may be effective in patients with advanced MMRd ACC and low cortisol levels.
Conflict of interest
None.
Support
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Mario Caccese*
Department of Oncology, Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
E-mail address: mario.caccese@iov.veneto.it
Fililppo Ceccato Endocrinology Unit, Department of Medicine DIMED, University-Hospital of Padova, Padova, Italy
Matteo Fassan, Ambrogio Fassina Surgical Pathology Unit, Department of Medicine (DIMED), University Hospital of Padua, Padua, Italy
Marta Padovan Department of Oncology, Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
Isabella Mammi Medical Genetics Unit, Dolo Hospital, Venice, Italy
Maurizio Iacobone Endocrine Surgery Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
Carla Scaroni Endocrinology Unit, Department of Medicine DIMED, University-Hospital of Padova, Padova, Italy
Vittorina Zagonel, Giuseppe Lombardi Department of Oncology, Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
*Corresponding author. Department of Oncology, Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
Received 6 December 2018 Accepted 15 December 2018
References
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