Marked Response of a Hypermutated ACTH-Secreting Pituitary Carcinoma to Ipilimumab and Nivolumab

Abstract

Context: Pituitary carcinoma is a rare and aggressive malignancy with a poor prognosis and few effective treatment options.

Case: A 35-year-old woman presented with an aggressive ACTH-secreting pituitary adenoma that initially responded to concurrent temozolomide and capecitabine prior to metastasizing to the liver. Following treatment with ipilimumab and nivolumab, the tumor volume of the dominant liver metastasis reduced by 92%, and the recurrent intracranial disease regressed by 59%. Simultaneously, her plasma ACTH level decreased from 45,550 pg/mL to 66 pg/mL.

Molecular evaluation: Both prospective clinical sequencing with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets and retrospective whole-exome sequencing were performed to characterize the molecular alterations in the chemotherapy-naive pituitary adenoma and the temozolomide-resistant liver metastasis. The liver metastasis harbored a somatic mutational burden consistent with alkylator-induced hypermutation that was absent from the treatment-naive tumor. Resistance to temozolomide treatment, acquisition of new oncogenic drivers, and subsequent sensitivity to immunotherapy may be attributed to hypermutation.

Conclusion: Combination treatment with ipilimumab and nivolumab may be an effective treatment in pituitary carcinoma. Clinical sequencing of pituitary tumors that have relapsed following treatment with conventional chemotherapy may identify the development of therapy-induced somatic hypermutation, which may be associated with treatment response to immunotherapy.

Figure 1.

(a) Volumetric measurements of the intracranial tumor and liver metastasis across the patient’s clinical timeline and corresponding measurements of ACTH show response to treatment with immunotherapy. (b) MRI scans of the intracranial and liver sites before and after combination treatment with ipilimumab and nivolumab, mirroring response in (a). CAPTEM, capecitabine/TMZ; Carbo/Etop, carboplatin/etoposide; Ipi/Nivo, ipilimumab/nivolumab.

Figure 2.

(a) Sample tree showing clonal relationship of the pre-TMZ primary specimen and the posttreatment liver metastasis, with numbers in circles indicating mutations acquired from the previous branch point. The two tumors share 15 mutations. The post-TMZ sample acquired a large number of private mutations, typical of therapy-induced hypermutation. Mutations considered likely oncogenic are highlighted. (b) The substitution types (colored labels) and trinucleotide context (vertical labels) of SNVs in both samples, as a fraction of total mutations. An enrichment for C>T/G>A transitions, characteristic of alkylator-induced hypermutation, was present in the posttreatment but not pretreatment sample. Numbers above bars indicate absolute number of mutations in that bin. (c) Estimates of fraction of cancer cells harboring mutations in both samples, represented as a three-dimensional density plot, showing the large number of mutations acquired in the post-TMZ sample. Whereas the mutation in MSH6 was nearly clonal in the liver specimen, the acquired mutation in PIK3CA was found in a minority of the cell population.