Immuno-oncology (IO) is an effective strategy for the management of non-glioma tumors and it may be enhanced in hypermutators. Hypermutator glioblastoma (HmGB) is seen as initial tumor diagnosis or at recurrence after temozolomide (TMZ) treatment. We describe clinical and molecular features of HmGB treated with IO.
Retrospective review at MD Anderson between Feb, 2012 through Feb, 2017 identified 312 gliomas with tissue analyzed by next-generation sequencing (T200-1, Oncomine, FoundationOne). HmGB was defined as histologically proven GB with tumor mutational burden (TMB-30) of 30 or more mutations (mut) per Mb, or displaying mut in mismatch repair (MMR) or DNA polymerase (Pol) genes.
30 (9.6%) patients had HmGB. From those, 9 (30%) received IO. 5 (55%) were men. Median age at HMGB diagnosis was 38 years (31-66). 7 (78%) had mut in MMR and 2 (22%) in Pol gene. 5 cases had IDH1 mut. 5 MGMT were umethylated. HmGB was found as initial diagnosis in 5 (56%) cases, the rest after TMZ. Of those patients with initial HmGB, 3 had MMR mut and 2 Pol mut. 8 had somatic mut and only 1 had germline MMR mut (Lynch Syndrome, MSH2, c.652C>T [p.Gln218*]). For post-treatment/recurrent HmGB, the most common alteration was MMR mut (N = 4). 8 HmGB patients received either CPI off protocol or cellular therapy (T-cells or NK cells) at recurrence of HmGB after TMZ, only 1 patient received CPI at initial HmGB diagnosis, concurrently with standard of care. In HmGB with somatic mut, OS from initial brain tumor and HmGB diagnosis was 39 and 22 months. PFS and 6m-PFS after starting IO was 72 days and 0% respectively. The PFS after TMZ, in those treated with CPI, reactive T-cells and natural killer cells was 51, 41 and 175 days, respectively, whereas the PFS in the one with newly diagnosed HmGB was 96 days. The median cumulative dose of pembrolizumab was 720 mg per patient. The patient with germline HmGB is on pembrolizumab and is the only one with stable disease for more than 12 months.
IO seems to be ineffective in HmGB with somatic mut regardless the onset of diagnosis (newly/recurrent) or type of Hm phenotype. However, germline HmGB may have durable responses to IO. Further investigation is needed to determine the potential antitumor immune response in this population.
The authors.
This work was supported in part by the Sheikh Khalifa Al Nahyan Ben Zayed Institute for Personalized Cancer Therapy, and the MD Anderson Cancer Center Support grant (P30 CA016672) MD Anderson Cancer Center.
All authors have declared no conflicts of interest.