The response of patients with pituitary tumors to immunotherapy has not been reported. Our recently published case study suggests that combination treatment with immunotherapy may be an effective treatment strategy, especially for tumors that are resistant to temozolomide (TMZ).
A 35-year-old woman presented at Memorial Sloan Kettering Cancer Center with an aggressive adrenocorticotrophic hormone (ACTH)–secreting pituitary adenoma. The tumor initially responded to concurrent TMZ and capecitabine but then metastasized to the liver. After five treatments with ipilimumab and nivolumab, the volume of the dominant liver metastasis decreased by 92 percent and recurrent intracranial disease regressed by 59 percent. At the same time, the plasma ACTH level dropped significantly, from 45,550 pg/mL to 66 pg/mL. (1)
To characterize the molecular alterations in the patient’s chemotherapy-naive pituitary adenoma and the temozolomide-resistant liver metastasis, we performed prospective clinical sequencing with MSK-IMPACT™ and retrospective whole-exome sequencing. This analysis revealed that the liver metastasis harbored a somatic mutation burden consistent with alkylator-induced hypermutation that was absent from the treatment-naive tumor, explaining the response to immunotherapy. (1)
Our results suggest that clinical sequencing of pituitary tumors that have relapsed after treatment with traditional chemotherapy can identify mutations that may respond to immunotherapy. However, the generalizability of this patient’s response to other patients with pituitary tumors requires further study. A clinical trial currently being developed at MSK to use checkpoint inhibition for treating patients with aggressive pituitary tumors will better define the patient population and shed light on which patients would most benefit from this therapy. (1)
Cushing’s disease is a rare endocrine disorder due to an ACTH-secreting pituitary tumor causing excess adrenal cortisol production. Most pituitary tumors are benign, but a significant minority behave aggressively, with recurrent and invasive growth. Up to 0.2 percent are malignant, characterized by the presence of noncontiguous craniospinal or systemic metastasis. (1) Median survival is one year. (3), (4)
Standard treatment relies on a combination of surgery, radiation therapy (RT), and two available medical therapies, which are usually ineffective. The two medical treatments are cabergoline, a dopamine-2 receptor agonist that reduces cortisol levels in 25 to 40 percent of patients with Cushing’s disease, (5), (6), (7) and pasireotide, a somatostatin analog that normalizes cortisol in about 13 to 25 percent of patients. (8) These therapies are usually employed for benign disease. They achieve only modest tumor reduction and have shown limited success in treating aggressive and malignant cancers.
Temozolomide (TMZ) is an alkylating agent approved for the treatment of glioblastoma. It has shown modest activity on pituitary tumors, with some data suggesting improved response with the addition of capecitabine. Many patients either do not respond or stop responding. As a result, there is a substantial unmet need for an effective treatment strategy for this patient population.
Results with Surgery, Chemotherapy, and Radiotherapy
The 35-year old woman presented initially in the fall of 2011 for management of a right third cranial nerve palsy, hirsutism, and weight gain. She was found to have a pituitary macroadenoma, elevated 24-hour urine-free cortisol values, and high plasma ACTH levels consistent with Cushing disease. Following two consecutive subtotal transsphenoidal resections, the residual adenoma grew in size over the next year, and she received fractionated RT. Within months, the tumor grew again, and the woman underwent a third and fourth transsphenoidal resection at 27 and 39 months after initial diagnosis. (1)
Due to further growth and incomplete hormonal control despite treatment with pasireotide, ketoconazole, and ketoconazole in combination with cabergoline, she was treated with concurrent TMZ and capecitabine. Treatment was discontinued after four cycles due to poor tolerance and thrombocytopenia. However, the patient had a biochemical and radiographic response to treatment: Her tumor decreased in size by 41 percent, and her ACTH level dropped from 266 to 80 pg/mL. (1)
Over the next two years, the pituitary adenoma remained stable in size. But the patient experienced worsening comorbidities due to the hypercortisolemia, including diabetes, hypertension, deep vein thrombosis, and pulmonary embolism. Treatment with mifepristone and metyrapone was unsuccessful. As a result, she underwent evaluation for bilateral adrenalectomy with a body CT, which revealed a suspicious liver lesion at 68 months after initial diagnosis. (1)
A biopsy of the tumor identified a high-grade neuroendocrine growth that was positive for ACTH and a mitotic index of up to 50 percent. Immunohistochemistry on the liver specimen for 0-6-methylguanine-DNA-methyltransferase revealed positive nuclear staining. Following bilateral adrenalectomy, the patient’s diabetes, hypertension, obesity, and cortisol-induced psychosis resolved, but the right third nerve palsy worsened. MRI of the pituitary tumor and brain found extension of the tumor along the tentorium, and an abdominal MRI showed rapid progression of the liver metastasis. After an additional two cycles of capecitabine plus TMZ, imaging found that the original liver metastasis had grown, and there were additional metastases. (1)
Results with Combination Immunotherapy
After further progression on two cycles of carboplatin and etoposide and RT to the intracranial component, the patient consented to investigational treatment with combination ipilimumab (3 mg/kg every three weeks) and nivolumab (1 mg/kg every three weeks). Five days after her first infusion of the combination immunotherapy, she developed a fever of 40 degrees Celsius and a mild transaminitis that resolved with a high dose of glucocorticoid. Within one week, her ACTH levels dropped tenfold, from 45,550 to 4,764 pg/mL. After five treatments of ipilimumab and nivolumab, the dominant liver metastasis shrank by 92 percent (415 to 34 cm3), the recurrent intracranial tumor decreased by 59 percent (3.9 to 1.6 cm3), and her plasma ACTH level dropped to 66 pg/mL. (1)
Between cycles five and six of ipilimumab and nivolumab, two of the smaller liver metastases enlarged in size but then stabilized or shrank, consistent with pseudoprogression on immunotherapy. The right third nerve palsy successfully reversed. After six months of follow-up and receiving maintenance doses of nivolumab, the patient continues to respond without additional immunologic adverse reactions and has an ACTH of 59 pg/mL at the time of writing our report. (1)
Clinical Sequencing Insights
The patient consented to participate in our ongoing clinical trial investigating the utility of MSK-IMPACT, a targeted sequencing platform covering 468 cancer-associated genes and select intronic regions to identify recurring gene fusion events. We prospectively tested the patient’s TMZ-naive pituitary tumor from the final transsphenoidal resection as well as the liver lesion that had been exposed to TMZ. We also performed retrospective whole-exome sequencing on the circulating DNA libraries generated by the MSK-IMPACT assay to compare results. (1)
MSK-IMPACT revealed no somatic mutations, a focal amplification of CCND3, and a homozygous deletion of PTPRD in the pituitary tumor. Overall, it had few mutations, typical of previously sequenced pituitary adenomas. (9) MSK-IMPACT results for the liver metastasis found not only the same CCND3 and PTPRD mutations but also 105 somatic mutations that were not present in the pretreatment pituitary tumor. (1)
To explore the clonal relatedness of these tumors in greater detail, we performed whole-exome sequencing on both samples along with a matched sample of normal tumor to distinguish somatic from germline mutations. We found that the pituitary tumor and the liver tumor shared 15 somatic mutations, revealing their common origin and clonal relationships. Neither tumor harbored a USP8 mutation commonly seen in ACTH-secreting pituitary tumors. (10)(,) (11)
Our analysis found that the TMZ-exposed liver metastasis was hypermutated, harboring 5,275 mutations that were not present in the pretreatment specimen. We identified a truncating homozygous MSH6 mutation that was present in most of the liver cancer cells but absent in the treatment-naive pituitary tumor and validated the findings with immunohistochemistry. The liver metastasis revealed additional cell cycle alterations, including a deletion at the CDKN2A/B locus and activation of the P13K pathway via a subclonal P1K3CA G1050D hotspot mutation, which was a direct result of mutagenesis induced by the alkylator chemotherapy. Germline analysis did not reveal any pathogenic allele that could explain the somatic hypermutation. (1)
Implications for Future Research
This case study suggests that checkpoint inhibition should be a treatment consideration for aggressive pituitary tumors and carcinomas, especially for tumors that have developed resistance to TMZ. An alkylating chemotherapy that creates 06-methylguanine adducts and induces apoptosis when a functional DNA repair system is present, TMZ can cause a mutation in the mismatch repair gene, resulting in hypermutations that may be associated with response to immunotherapy.
MSK-IMPACT was developed by bioinformaticians, molecular pathologists, and genome scientists at MSK and has been employed to analyze tumors in patients with advanced cancers since January 2014. Originally used to detect gene mutations in melanoma, lung cancer, and colon cancer, its use was expanded with the November 2017 authorization for the detection of mutations in any solid tumors regardless of origin.
MSK-IMPACT is available for MSK patients only. Currently, the panel covers 468 genes, and we continue to expand the panel as our knowledge base grows. All patient-level clinical and genomic data used in our analyses are deidentified and shared with the scientific community via the cBioPortal for Cancer Genomics, a portal developed originally at MSK and hosted by the Marie-Josée and Henry R. Kravis Center for Molecular Oncology at MSK. We also share data through AACR Project GENIE (a project by the American Association for Cancer Research called the Genomics Evidence Neoplasia Information Exchange), a collaboration among eight leading cancer centers that are pooling resources to take advantage of the genomic sequencing of tumors to advance precision oncology.
Based on this publication, the MSK Multidisciplinary Pituitary and Skull Base Tumor Center will be launching a phase II clinical trial to test the use of ipilimumab and nivolumab to treat aggressive and malignant pituitary tumors. Genomic analysis and immunophenotyping of the tumors will be included to explore mechanisms of response. As MSK is the only pituitary center using immunotherapy to treat pituitary tumors, we hope to attract referrals from other hospitals in the area.
One of the co-authors, Michael Postow, MD, is on the scientific advisory board and has received honoraria from Bristol-Myers Squibb. The remaining authors reported no disclosures.