In our case, we found two valuable points. First, the patient with DMG responded to olaparib combined with bevacizumab and achieved complete remission. Radiotherapy is the main treatment for DIPG and treatment method of DMG is limited at present, so it’s urgent to explore effective therapeutic strategies. PARP inhibitors have been used well in ovarian cancer, breast cancer and prostate cancer . Recently, multiple studies on PARPi have highlighted that therapeutic responses are irrespective of BRCA1/2 status or HRD [16–19]. This new evidence may extend the clinical use of PARPi toward a wider group of patients, especially those with BRCA1/2 wild-type. Olaparib plus bevacizumab have been used in ovarian cancer . Hypoxia caused by antiangiogenic therapy can induce or at least increase homologous recombination deficiency (HRD), which means that bevacizumab may increase HRD positive tumor patients [14, 20].
TP53 is a tumor suppressor gene in DNA damage pathway by preventing cells from entering the DNA synthesis phase, inhibiting cell division and proliferation, and allowing sufficient time for DNA damage to repair, and the TP53 mutations may benefit from olaparib therapy. M237I is located in TP53 DNA binding domain, which can result in the reduction of TP53 trans-activation activity . TP53 was reported as the candidate biomarkers of PARPi-mediated radiosensitization . Clinical trial (NCT02576444) is under way for AZD1775 plus olaparib to treat patients with tumors harboring TP53 mutations.
Second, we firstly identified a novel H3F3B K27I (the same as K28I) mutation in the adult DMG patient. DMGs with H3 K27M-mutant are a novel entity, which previous diffuse intrinsic pontine glioma belongs to and a mean survival of this tumor is only ∼9 months . H3 K27M-mutation are common in adult midline gliomas, but survival may be similar or improved if the mutation is present . It is important to identify H3 K27M-mutation accurately for accurate diagnosis, prognostication, and may also for treatment selection. Clinical trials with mutation-specific are ongoing (NCT03295396, NCT02717455, NCT03696355).
K27M mutation always occurred in H3F3A gene or HISTIH3B/C gene. K27I in H3F3A has been reported that also created a loss of trimethylation . H3F3B gene, like H3F3A, is also encodes histone H3.3 and expressed throughout the cell cycle. This is the first report of identification of the novel H3F3B K27I mutation in an adult DMG patient by NGS, which may expand the detection gene spectrum of DMG patients. However, the effect of the H3F3B K27I mutation on histone H3 and on glioma grading needs further study.
In conclusion, this is the first report of DMG patient responding to olaparib combined with bevacizumab and achieve complete remission. Our case report provides a promising option for DMG patients and provides direction for the design of future clinical trials.