NEW YORK – Treatment of pediatric medulloblastoma is still awaiting precision approaches, but a series of case studies published last month featured a way that, with more research, could help personalize treatment decisions for patients with this type of cancer.
In the case study series published in JCO Precision Oncology, researchers examined how germline and somatic mutations in patients with medulloblastoma impacted their outcomes on radiation therapy. One patient had germline ATM-mutant medulloblastoma and two patients had somatic ATM-mutant medulloblastoma. While the researchers cannot draw definitive conclusions about the role of germline versus somatic ATM mutations based on the experience of just three patients, Rebecca Ronsley, senior author of the study and pediatric oncologist in the brain tumor program at Seattle Children's Hospital, said the series highlights the "importance of an integrated diagnosis" for medulloblastoma that is inclusive of tumor histology and molecular features.
Among the three cases, the patient with a germline ATM mutation experienced adverse and delayed effects from radiation treatment. The 8-year-old girl initially tolerated standard radiation treatment well, but nine months post-therapy, she developed radiation-induced necrosis. The patient's symptoms progressed, and she later died of progressive respiratory failure.
The case series also included two medulloblastoma patients whose tumors harbored somatic, biallelic, inactivating ATM mutations and who also received standard-of-care surgery followed by radiation therapy. These patients, in contrast to the girl with the germline mutation, did not experience the same adverse outcomes from radiation treatment. In fact, both responded well and had no signs of delayed radiation-induced necrosis in follow-up scans.
The researchers hypothesized that the germline ATM mutation, which was identified by genetic sequencing of peripheral blood samples rather than a resected tumor sample, may have played a role in the first patient's radiosensitivity. Prior reports, they noted, have suggested that germline ATM mutations are associated with an increased risk of radiation toxicity or recurrence in patients with breast cancer and non-small cell lung cancer. However, this same risk has not been reported in medulloblastoma patients.
"For this particular mutation, it was less about the effect on medulloblastoma and more about the effect on radiation treatment sensitivity," Ronsley said. "We think [the germline ATM mutation] contributed to that patient's sensitivity to radiation."
Tom Rosenberg, an attending physician in pediatric neuro-oncology at Boston Children's Hospital who was not involved with the research, noted that this case series adds "valuable information" about the potential role of germline ATM mutations in medulloblastoma, "especially given the very rare and significant treatment-related toxicity seen in patient 1."
"In the broader context of cancer treatment, there seems to be conflicting evidence on the significance of ATM mutations and the risk of radiation-induced necrosis, with [a] paucity of data to differentiate germline and somatic mutations," he continued, adding that there is not much high-level evidence yet to support this association.
When diagnosing medulloblastoma, molecular and pathological features are used to classify patients into one of four subgroups: wingless-activated (WNT), sonic hedgehog-activated (SHH), group 3, and group 4. The WNT subgroup has an excellent prognosis and the majority of patients have a CTNNB1 mutation. Most patients in the SHH subgroup have germline or somatic mutations or copy number alterations in the SHH signaling pathway. Patients in groups 3 and 4 don't have shared molecular features and typically harbor rare genetic alterations. Medulloblastoma patients in group 3 tend to have the worst prognosis.
The patient with a germline ATM mutation was in the WNT subgroup and would be expected to have the best prognosis based on the above classification criteria. She was also classified to have an average risk of recurrence. One of the patients with a somatic ATM mutation was in the SHH group and thought to be at high risk of recurrence and the other patient was classified as non-WNT/non-SHH subgroup, or group 4, and considered to have an average recurrence risk.
These cases suggest to Rosenberg that the biology defining current medulloblastoma subgroups and associated clinical prognoses need to be understood better and highlight the need for precision oncology approaches due to medulloblastoma's "complex molecular landscape."
"[The case series] highlights our growing understanding of medulloblastoma heterogeneity, with each case belonging to a different subgroup," Rosenberg said. "The subgroups differ in their biology, as well as in clinical outcomes — patient 1 with a standard-risk WNT-driven tumor was expected to have an excellent outcome, while patient 2 in the SHH subgroup and high-risk group [is expected to have] a relatively poor outcome. This goes to say that extrapolation from one patient to another may be very challenging."
Previous research has explored the effect of these subgroups on treatment outcomes. Results from one Phase III trial from 2021 found that patients with group 3 medulloblastoma had the greatest improvement in outcomes when their treatment was intensified by adding chemotherapy to radiation treatment. Another Phase III study explored whether a lower-dose radiation therapy could be used to treat medulloblastoma. They found that patients in group 4 appeared to benefit more from a lower dose of craniospinal irradiation and had lower rates of recurrence or relapse within five years.
ATM mutations have not been previously reported to affect treatment outcomes in medulloblastoma as far as both Ronsley and Rosenberg were aware. Ronsley suggested that with further research into the role of germline ATM mutations in this setting, they could become part of the diagnostic process alongside the subgroup classifications and other clinical factors.
"Right now, [the presence of] a germline ATM mutation alone is not changing how we treat patients," she said. "But in combination with other individual patient factors, it may [change] in the future."
Rosenberg said he will likely keep in mind the possibility that medulloblastoma patients with germline ATM mutations may be at increased risk for radiation necrosis after reading the case series but agreed that it's too early to consider changing treatment. "Craniospinal irradiation is necessary in order to maintain favorable outcomes for patients with medulloblastoma, and I wouldn't consider omitting it even if an ATM mutation is found," he said.
Ronsley said Seattle Children's Hospital will continue exploring the role of tumor and germline mutations in pediatric cancers. The institution's precision oncology program conducts paired analyses with somatic and germline mutations to better understand how these variants affect cancer development and outcomes.
"We don't draw strong conclusions from individual cases, but in this case, we were able to identify a germline change in ATM that may have been a relevant factor to consider when determining the best therapy for her tumor," Ronsley said. "We wanted to describe it together with two other cases of pediatric medulloblastoma where the same genetic alteration was seen in the tumor, but not in the germline, to show the importance of doing molecular analysis in both the tumor and the germline in the pediatric population."