February 2019 Case

Authors

Fellow: Gaurav Khullar, MD. Faculty: Eric Vail, MD and Jean Lopategui, MD.

Subject: Molecular Pathology
Clinical History

The patient is a 35 year old male with a past medical history of anaplastic astrocytoma (Figure 1) status post treatment with temodar (TMZ) who presented with a recurrence of glioblastoma multiforme (GBM) (Figure 2). Next generation sequencing using the Cedars Comprehensive 161 gene panel was performed on the GBM specimen. Numerous mutations (38), including an inactivating PMS2 mutation, were detected. The result summary and tumor mutational burden are in Figure 3 and Figure 4, respectively.

Figures
Anaplastic astrocytoma 20x

Figure 1: Anaplastic astrocytoma (20x)

Glioblastoma multiforme 20x

Figure 2: Glioblastoma multiforme (20x)

Next generation sequencing Results Summary

Figure 3: Next generation sequencing Results Summary.

Tumor mutational burden

Figure 4: Tumor mutational burden (TMB)

Diagnosis

Glioblastoma multiforme with TMZ induce hypermutation

Discussion

In the setting of treatment with TMZ or other alkylating agents, the large quantity of mutations seen may be due to induced hypermutation. TMZ is a prodrug that when activated produces mutagenic O6 guanine residues. These residues cause coding errors that are normally corrected by the MGMT DNA repair protein and the DNA mismatch repair pathway. However, if an acquired mutation occurs in one of the DNA mismatch repair genes (eg: MLH1, PMS2, MSH2, MSH6), the mismatch repair pathway is unable to correct these coding errors. As a result, the tumor exists in a hypermutated state.

This is of clinical importance because tumors that have a high mutational burden and/or have a mismatch repair deficiency may be responsive to the PD-1 inhibitor pembrolizumab. Additionally, in May of 2017, the FDA approved pembrolizumab as second line treatment for patients with tumors in any site that are mismatch repair deficient.

Two case reports have shown that patients with hypermutated GBM show response to PD-1 inhibitors. In the first, two siblings with germline biallelic mismatch repair deficits and hypermutated GBMs demonstrated clinically significant response to nivolumab. In the second, a patient with germline POLE mutation and a GBM that developed metastatic disease to the spine after receiving TMZ and chemoradiation demonstrated a clinically significant response to pembrolizumab.

References

Choi, S., Yu, Y., Grimmer, M. R., Wahl, M., Chang, S. M., & Costello, J. F. (2018). Temozolomide associated hypermutation in gliomas. Neuro-Oncology, 20(10), 1300-1309. doi:10.1093/neuonc/noy016

Finocchiaro G, Langella T, Corbetta C, Pellegatta S. Hypermutations in gliomas: a potential immunotherapy target. Discovery medicine. 2017; 23(125):113-120. [pubmed]

Immune Checkpoint Inhibition Is Effective in Hypermutant Glioblastoma. (2016). Cancer Discovery, 6(5). doi:10.1158/2159-8290.cd-rw2016-060

Johanns, T. M., Miller, C. A., Dorward, I. G., Tsien, C., Chang, E., Perry, A., . . . Dunn, G. P. (2016). Immunogenomics of Hypermutated Glioblastoma: A Patient with Germline POLE Deficiency Treated with Checkpoint Blockade Immunotherapy. Cancer Discovery, 6(11), 1230-1236. doi:10.1158/2159-8290.cd-16-0575

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