ASCO: Molecular Diagnostics Allow Further Understanding of Medulloblastoma

Torunn I. Yock, MD

As part of our coverage of the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting, Cancer Network is speaking today with Torunn I. Yock, MD, director of pediatric radiation oncology at Massachusetts General Hospital in Boston. On Monday, June 2, Dr. Yock will serve as the chair for an Education Session titled “Medulloblastoma: Modern Molecular Diagnostics and Clinical Decision Making.”

-Interviewed by Leah Lawrence

Cancer Network: Dr. Yock,to provide some background, can you tell us how modern molecular diagnostics have increased the understanding of medulloblastoma in recent years?

Dr. Yock: Absolutely, I think there has been an explosion of understanding in what is going on now in medulloblastoma. We are finding that the more we know, the more we realize there is more to know. Specifically, we now can better categorize our medulloblastoma patients into risk categories. Although, I think more work needs to be done.

As little as about a decade ago, we only had three variants of medulloblastoma: nodular/desmoplastic variant, which seemed to have a bit of a better prognosis; the classic medulloblastoma histology; and the anaplastic or large-cell variant of medulloblastoma. The anaplastic large-cell variant proved to be the variant that connotes a worse prognosis. As we better understood that, we were better able to risk stratify our patients.

We basically have two risk groups, a standard risk and high risk. We now know to exclude the anaplastic large-cell variant patients from the standard-risk category, and we often include them in the high-risk category, but it is not clear that all of them are truly high risk. We have a better understanding that they are not likely to do quite as well as the classic or desmoplastic variants.

Most recently, however, in the last 5 or so years, we have come to understand that these histologic classifications are really just gross markers for what is happening on a molecular basis. We can further par this group down into four groups. The first is the WNT pathway variant, which is a beta-catenin, and this group tends to do very well with the therapies we give them. The second group is called the sonic hedgehog group, the SHH group, that goes along with the classic event-free survival of about 80%. That is how we tend to think of the standard-risk patients, as falling into the sonic hedgehog pathway group. Then there are two groups where the prognosis is more guarded: Group C and Group D. We are better characterizing these groups. Group C tends to have Myc amplification, either n-Myc or c-Myc, but mostly c-Myc. Group D is a mish-mash of a variety of molecular subtypes.

Cancer Network: How has the subclassification of the disease changed the approach to treating the disease with chemotherapy, radiation, or, in some cases, both treatments?

Dr. Yock: We are in the infancy of knowing exactly what to do with this subclassification. I think with the WNT pathway medulloblastomas we can start backing off of therapy since the cure rates are between 90% and 100% for these patients. We probably can back off on the craniospinal dose, which we know is toxic in these pediatric patients, and even adult patients. Some institutions are undertaking studies looking at the backing off of therapy in this group. I believe St. Jude Children’s Research Hospital and Dana-Farber Cancer Institute are starting to back off on the radiation doses.

With regard to what to do with sonic hedgehog pathways and Group C and Group D, it is a little less clear. The sonic hedgehog pathway is exciting because there are two targeted agents that can be used in this disease. Right now we are still in the deployment phase for recurrent medulloblastoma of the sonic hedgehog pathway and are trying these drugs out in these patients. There is some risk for side effects, so before we move into the upfront treatment paradigm, we want to make sure it is safe in the pediatric population. I think that is what will be coming down the line, but we are unlikely to back off on therapy for the sonic hedgehog pathway patient population until we can improve on the 80% disease-free survival rate in the standard-risk population. The standard risk and the high risk are determined by the presence of significant residual disease at the time of adjuvant radiation and chemotherapy after surgery or the presence of metastasis. It is really the metastasis that drives the worse prognosis. Group C and Group D patients tend not to do quite as well. I think it is definitely clearer that the Group C patients have a much more guarded prognosis. I do believe that studies that are undertaking risk stratification at this point in time are going to be escalating the intensity of treatment with both radiation and chemotherapy, at least in Group C. In Group D, we are still trying to figure out if we can subcategorize it better and figure out who is going to do well and who is going to do badly. We are still on the learning curve, but I think we are at least beginning to be able to risk stratify better than we have in the past.

Cancer Network: Looking forward, what additional advances do you hope further molecular understanding of the disease might bring to these patients?

Dr. Yock: The more we learn about the various pathways that drive these tumors, the better we will be able to target therapies to treat them. We previously thought of medulloblastoma as all one disease and treated it accordingly. We realize now that that is simply not true. As we can figure out what drives each medulloblastoma, we can better target our therapies. We are still quite a few years away from that, but we are beginning to see agents that are useful and able to target the various pathways. I think we will be testing these for safety and then moving them into the upfront de novo diagnosis paradigm, but we first have to test them in the recurrent setting.

Cancer Network: Thank you for taking a few minutes to speak with us today.

Dr. Yock: Thank you very much, it has been a pleasure to talk with you.