Dr. Cloughsey
Primary Brain Tumors: Incidence
Close to 40,000 new cases in 2002
60% are high grade = poor prognosis
50% increase in incidence since 1984
Gliomas can have devastating function
People over 65 had highest increase in brain tumors
Molecular and genetic considerations
Causes -
Unknown
(small percentage) Increased incidence in farmers, ham radio operators, nuclear industry worker, petroleum field workers and those exposed to radiation to central nervous system
Hot issues: aspartame and cellular phones (unknown risk - no supportive data exist - we think the answer is no)
5% related to inherited genetic condition
19% report family incidence of cancer
Molecular Biology -
DNA stored in every cell and gets replicated when cells are made (kind of like blueprint)
RNA only made if cells wants to make something for that cell. Small percentage of DNA used to make RNA. Acts as an assembly line, adds amino acid into complex string that turns into a protein that goes in cell and interacts with other cells (this is where you get the cells that are made for specific functions, heart cell, brain cell, etc.)
In any tumor, there are abnormalities that occur in the DNA, mutation or loss in gene which can work on the protein and when activated to create new cells, it gets knocked out and then you have reproducing cells with abnormality. This can happen in any kind if cell brain, breast, etc.
Brain cancer is molecularly heterogeneous (they might look the same under the microscope, but they are different in behavior)
Primary brain tumors are classified according to the cells of origin
Malignancy determined by cellular characteristics
Primary gliomas do not spread outside of the central nervous system (except in rare cases)
- astrocytoma (Grade 2)
- anaplastic astrocytoma (grade 3)
- glioblastoma multiforme (grade 4)
features to determine grading:
pleomorphism
mitosis - cells actively dividing
endothelial proliferation (new blood cells forming)
necrosis (cell death)
astrocytoma can accumulate abnormalities and increase in grades
some tumors right out of the gate are grade 4
features on imaging give insight as well, Mark's tumor looks like it was the type that has been around for a long time and eventually changed grade over time vs. one that was GBM right out of the gate, because it was well defined instead of diffused. Typically, Mark's kind has better survival rate.
tumors look the same but have very different expression of genes and different survival
we can select antibodies that will look for specific protein and see if exists or not in tumor cells (PTEN and other types of proteins), we can see if metabolics pathway has been activated or not and we can characterize which pathways have been activated that can help us choose therapy. There are agents that can block certain pathways if activated or driving tumor.
Proneural, proliferation, met
How do we individualize therapy? This is what we're actively working on at UCLA.
Signs and symptoms
Headaches most common initial system
Seizures about ½ of patients have some type of seizure
Mental changes - memory, speech and communication
Nausea and vomiting; drowsiness, vision problems, blurred or double vision (usually cause by increased intracranial pressure that can be due to tumor's growth within skull, blockage of cerebral spinal fluid that flows through ventricular system or edema of the brain around the tumor (fluid leaking outside of contrast enhancing area)
Brain stem tumor - clumsiness, swallowing, double vision, hearing loss, anything effecting cranial nerves, headache on awakening
Cerebral hemisphere tumor
- frontal lobe tumor (unilateral paralysis, memory, impaired judgment, personality, mental changes)
- occipital lobe tumor - blindness in one visual field
schwannoma -
meningioma - growing off base of skull, don't change that rapidly, 20% of all primary brain tumors, slow growing, arachnoidal cells,
medulloblastoma - typically in children, in 4th ventricle, in cerebellum, doesn't spread outside of CNS, needs spine radiation as well as brain
astrocytoma/glioma - can grow rapidly,
MRIs can detect better than CT scans
New PET imaging - typically use glucose as a tracer, now trying thymidine or dopa(goes past blood brain barrier and goes into any area that is tumor, can show low grade tumors too, good for after surgery because you can identify tumor activity vs. scarring) as tracers now that reflect cell proliferation (rapidly dividing) Usually only available for patients on clinical trials.
What are you learning from GBM survivors? We're big progression if seeing if molecular makeup helps determine survival.
MRSpec - can get lots of false reads because of volume averaging
Radiation therapy
Conformal
Focused: seeds, sterotactic, proton
Sensitizers - not a confirmed effective sensitizer for brain radiation
30% progression
27% stable disease
43% shrinkage of tumor
Chemotherapies effective for malignant gliomas?
Try to cause abnormality in DNA so it can't replicate
In the past, chemo didn't seem to have much effect in GBM; however, Temodar seemed to have some radiation sensitizer effect and studies now show the Temodar/radiation combo has a noticeable improvement over radiation alone. (26% increase in 2year survival)
Different tumors respond differently to different agents. The most effective approved chemotherapies are CARBO(alkylating/cross linking), BCNU(alkylating agent), CPT-11(topoisomerase I inhibitor), TEMODAR(alkylating/methylating), PCV combination chemotherapy, VP-16(topo
Unfortunately, we don't yet have good ways of knowing which ones will work for the different tumors and have to do trial/error most of the times.
Biologic Agents
Tamoxifen, Accutane, b-interferon,
Cytostatic agents plus Temozolomide
Saw some significance with marinated, but couldn't be repeated in successive studies, many times there hasn't been a significant benefit overall
Vascular endothelial growth factor
Avastin/cpt11 (approved for colon cancer, breast) Avastin side effects could be local hemorrhage (1 in 30) which is why they are concerned about using it in the brain; high blood pressure, proteinuria; cost - many health plans don't pay because it isn't approved for GBM (could be $5-10 thousand dollars every 2 weeks), Duke is doing a trial for this and UCLA is managing about 65 patients on this trial (our friend Tom is trying out this new chemo combo), given every 2 weeks. Preliminary data shows 51% have shrinkage of recurrent GBM
Molecular evaluations on tumors
Not always that reliable, so it makes it difficult to provide guidance. This is the type of information that will be coming soon to help guide therapy. Molecular biology has helped in oligodendroglioma tumors because they could see if there were big chunks of genes missing in 1st chromosome that patients did better when this chunk was gone, and those with it present didn't do as well. Helps with prognostic information, but not treatment. We know that genes are missing, but we don't know which ones - but some how important that it is missing? Not useful enough in clinic to determine treatment. We're trying to find similar data in GBM patients to find out what chemotherapies will work better than others for specific patients. Findings that ones with methylated MGMT did better than patients whose gene is not methylated, but this hasn't been validated.
How do you decide which inhibitor to give to a GBM patient? There isn't just one thing to target. There could be several pathways that are driving the tumor to grow. We try EGFR, mTor or others as prohibitors, but not sure if we're going to get an effect. Studies show that some patients do have positive results in a minority of patients. Tested EGFR/PTEN molecular features of tumors and found that when both expressed, it identifies the responders and could help identify if you should be using growth factor receptor or not. (Mark's tumor didn't show these, so that we know Tarceva probably wouldn't be a good prohibitor for him).
We are getting closer to individualized therapies. We are beginning to identify subgroups.
