Wednesday, 19 April 2017

Oligo 2 meeting with Patrick Wen


I met with my NO Dr. Patrick Wen who is director of Dana Farber NO department yesterday. While I 'm stilling awaiting surgery, and therefore pathology, Dr. Wen feels my tumour is most likely an Oligo 2. It is 3cm in left left frontal lobe. I'm 35.

Dr. Wen told me most of these will recur around 10 years (for this location, size, my age, and depending on resection, etc). He also said he believes it's not unrealistic to think that by then there'll be an effective therapy to stop IDH mutant tumours from growing, essentially turning it into a chronic condition. He has a low grade patient (or more) who he was meeting with before me who has been on and IDH inhibitor for a year and a half now. Those seemed to be most promising to him.  He also mentioned PARP inhibitors and a number of other promising agents. He named about 6, including demethylating agents which seemed like a new idea.

I thought I'd share, because it was really helpful to me. He is very optimistic. He said that all of NO is focused on this mutation right now.

I know that's not useful to others without the mutation. Sorry.

I also thought I'd share his video addressing the recent WHO reclassification of these tumours. Most people on here  probably know this but on other blogs it seems a lot of people do not. Their type of tumour may have been essentially misdiagnosed all along.

It's my understanding that there is no longer a grey area. You must have co-deletions and IDH mutation to have an Oligo. Without the co-deletions it's an Astrocytoma and without IDH mutation it's a glioblastoma. I often see things that read "80% of Oligos have co-deletions (or IDH mutation)" but you can no longer be diagnosed with an Oligo if it doesn't have these characteristics. Grading is then related to not yet malignant (low grade) or malignant (high grade). I also believe they can lose their co-deletions, progressing to and Astrocytoma but are not likely to lose the IDH mutation. Maybe Stephen, or others, will be gracious enough to let me know if I have this correct.

I'm curious to know how likely Pligos are to lose their co-deletions upon first recurrence. I'm not sure this information is available.



  1. For the most part you are correct. Diagnosis is becoming more dependent on genetics rather than histopathology (the appearance under the microscope). So for example, even if the tumor cells look like oligodendroglioma cells, but the tumor has IDH1, TP53 and ATRX mutations and no 1p/19q co-deletions, it will be diagnosed as an astrocytoma rather than an oligodendroglioma.

    However, oligos rarely if ever turn into astrocytomas, genetically. Oligos generally stay oligos. Also, 1p/19q codeletions are usually (always?) retained at recurrence.

    See studies such as:
    Genetic and epigenetic stability of oligodendrogliomas at recurrence

    To clarify a little, a low grade glioma without IDH mutation is not necessarily a glioblastoma. It could be a grade 1 pilocytic astrocytoma or some other genetic type unrelated to the standard adult type GBM. There are also cases where the proper testing can't be done, leading to a diagnosis such as astrocytoma or oligodendroglioma or glioblastoma NOS ("not otherwise specified"). This NOS designation would especially be applied if testing for IDH1 mutation was not performed.

    1. Thanks, Stephen. Can you say anything about progression to malignancy? This study says that they seldom become aggressive.

      Also, what are your feelings about his optimism about turning this into a chronic, controlled condition? I did read the on the AO website the IDH inhibitors seemed particularly promising.


    2. The text of the study says that two of the grade 2 oligodendrogliomas progressed to grade 3 at recurrence and one stayed at grade 2 at recurrence. Though this was only a small cohort (12 patients), it does indicate that progression from grade 2 to grade 3 oligodendroglioma is not uncommon.

      What is uncommon is for an oligodendroglioma to progress to a grade 4 tumor. Even hypermutated oligodendroglioma recurrences (there is a 50-60% chance of this happening following therapy with temozolomide alone) tend to recur as grade 3 rather than grade 4.

      I'm optimistic too, especially for lower grade oligodendrogliomas. Mutant IDH1 inhibitors such as AG-120 seem more promising for low grade tumors than high grade, although we have only preliminary phase 1 data so far.

      It's too early to say what the most effective strategy will be, but there is a lot in trials and still to be tested: small molecule IDH inhibitors, IDH1 R132H vaccines, PARP inhibitors, DNA demethylating agents, etc. and it remains to be seen which combination of therapies will turn this into a chronic condition, but I too believe that it will happen. The IDH1 mutation was only discovered less than 10 years ago and rapid strides have already been taken.

    3. "World Health Organization histological grade at recurrence was mostly stable; it was increased in 2, the same in 9, and decreased in 1 cases."

      Is this the area of the abstract that indicates which progressed and which did not?

    4. No, that part isn't in the abstract. You can read the full study by clicking on the link in pubmed where it says "Full text links"

      Or you can go here to read the full text:

  2. I was just wondering about oligo - astro change at recurrence the other day. For example I read about Anders Ferry - as far as I know he was initially diagnosed with anaplastic astrocytoma, then had a oligodendroglioma recurrence somewhere in between. I found more cases like this on various patient blogs, with recurrence being genetically different than initial tumor.

    Then last week I read about "Incidence and survival trends in oligodendrogliomas and anaplastic oligodendrogliomas in the United States from 2000 to 2013: a CBTRUS Report". There it states: "Here, we report a decreasing trend in overall OD and AOD incidence from 2000 to 2013...We observed significant decreases in OD and AOD...The decreasing trend from 2000 to 2013 may suggest that the purported increase in OD and AOD incidence as a result of neuropathologist
    bias has not withstood the test of time. Additionally, this decline over time could indicate a tightening of the histopathological classification of oligodendroglial
    tumor types based on increasing implementation of molecular diagnostics."

    So I think there may be quite a few misdiagnosed "oligodendrogliomas".

    About recurrences - yes, it is highly likely it will recur. But maybe not :)

    Gliomas: Survival, origin and early detection
    "To be sure, there are some gliomas that we can cure with modern surgical techniques, such as pilocytic astrocytomas, the occasional oligodendroglioma, neurocytomas, gangliogliomas, subependymomas and a few xanthoastrocytomas and protoplasmic astrocytomas."

    The effect of extent of resection on recurrence in patients with low grade cerebral hemisphere gliomas. (although from 1994)
    "Our results suggest that patients with low grade gliomas and a tumor volume greater than 10 cm3 benefit from radical surgery at the time of
    radiographic diagnosis in terms of influencing the incidence of recurrence, time to tumor progression, and malignant transformation.
    It may be that the biology of large (i.e., > 30 cm3) low grade gliomas
    is quite different from smaller tumors. We have not seen recurrences
    in patients with tumors less than 10 cm3." (although followup here was only 24-121 months).

    Long-term outcomes after supratotal resection of diffuse low-grade gliomas: a consecutive series with 11-year follow-up

    This is retrospective study of dr. Duffau. Half patients recurrence free at 8-16 years follow-up. All patients with volume <10 cm3 recurrence free.

    I remember another study which I can't find right now, where they were assessing "risks" of LGG recurrence. The biggest risk was tumor size 3cm or more.

    Anyway, just wanted to share some "positive" articles. I was also in contact with 3 patients 14, 18 and 23 years after surgery, all rc free.

    1. Diagnostic revision of 206 adult gliomas (including 40
      oligoastrocytomas) based on ATRX, IDH1/2 and 1p/19q status

      "All oligodendrogliomas kept the initial diagnosis"

      "Astrocytomas did not change diagnosis in 30 of 36 cases (83.3 %); four of 36 (11.1 %) cases were reclassified as oligodendroglioma"

      "Oligoastrocytomas changed diagnosis in 35 of 40 (87.5 %) cases"

      It's important to realize that diagnoses based on morphology/appearance of the tumor cells is much more fluid than diagnoses based on genetics. Also "astrocytoma" is more likely to be reclassified as "oligodendroglioma" than vice versa. And "oligoastrocytoma" can usually be reclassified as either astrocytoma or oligodendroglioma based on genetics (with rare exceptional cases of true mixed genetics where the founding mutant IDH1 clone evolves down both astrocytoma and oligodendroglioma genetic pathways as distinct subclones).

      Thank you for sharing those long-term survival statistics, that is always good to hear!

    2. See also Figure 2 from this study:
      "ATRX and IDH1‑R132H immunohistochemistry with subsequent
      copy number analysis and IDH sequencing as a basis for an
      “integrated” diagnostic approach for adult astrocytoma,
      oligodendroglioma and glioblastoma"

      I can upload any of these studies to the library if anyone wants to read them in their entirety.

    3. I forgot to paste another study, which I think has one of the longest follow-ups:

      Intracranial low-grade gliomas in adults: 30-year experience with long-term follow-up at Mayo Clinic

      It includes 314 patients. Overall, the median follow-up was 13.6 years. Recurrence was documented in 174 patients who had a median time to progression of 7.2 years and a median PFS of 5.0 years. The 5-, 10-, and 15-year PFS rates were 50%, 27%, and 17%, respectively. This includes all histologies (OG II was diagnosed in 11%) and all extents of resection (GTR was achieved in 13%, with 41% subtotal resections and 35% biopsies only).

  3. Dual-Genotype Diffuse Low-Grade Glioma: Is It Really Time to Abandon Oligoastrocytoma As a Distinct Entity?

    It seems it is also possible to have two different areas in a tumor, where one corresponds to oligo and one to astro genotype.

    Maria, if you don't mind me asking - do you know how your doctor is assuming you have oligodendroglioma from a MRI picture?

    1. He doesn't say with 100% confidence but that's how he leans. I can't really say why, other than he's one of the top in this field. I thought I read that co-deletions can be detected on MRI somehow and 2-HG can be too.

      It seems many, but not all, long term survivors had them removed from temporal lobes. Where they can remove more tissue. But my NO does have a patient diagnosed at age 45, left frontal lobe who is recurrence free now at age 70. It seems all NO's have a story like that.

    2. (Co-deleted) oligos tend to have indistinct tumor borders - according to one of the latest articles. But in the past (older articles) indistinct border was associated with astrocytoma and distinct border with oligodendroglioma.

      I think most tissue can be removed from frontal lobe in non-dominant hemisphere.

      See figures 3 and 4 - resection probability of left/right sided gliomas

  4. I also have the IDH1 mutation. My doctor told me the results for treatments that target IDH1 weren't as good as they'd hoped for, which is not unexpected for targeted treatments.

    1. A number of studies say these will have to be overlapping approaches and there are a number of weaknesses to exploit with the mutation. I just looked at a trial, just updated March 2017, that used three techniques. Who is your NO, if you don't mind my asking?

    2. I am generally a proponent of combination therapy, but in some cases there are strategies that shouldn't be combined. For example, pretreating an IDH-mutant glioma with a mutant-IDH1 inhibiting drug would likely cancel out the sensitivity to PARP inhibitors, which is dependent on 2-hydroxyglutarate.

    3. I have high hopes for immunotherapy targeting cancer stem cells. ICT-107 which targets some of the antigens, showed this approach can be successful in some subset of patients.

      From astrocytomaoptions (for GBM patients): Of the 16 newly diagnosed patients in this trial, 6 (37.5%) are still alive at 100 – 123 months (8.3 – 10.25 years). 3 patients (19%) are without progression at 100 – 118 months (8.3 – 9.8 years).

      Results from one of the latest studies suggests that CSCs do exist in oligodendroglioma and that targeting these cells would be highly beneficial. Coupled with checkpoint inhibitors (PD1 or maybe new ones being developed - TIM-3,...) and maybe IDH1 inhibitors (which seems to cause further immunosuppression) there would maybe be more responders than in phase 1 (or 2) trial of ICT-107.

    4. ICT-107 results in GBM have been quite good. ICT-107 is a combination of 6 peptides from GBM-associated antigens. I've never seen any investigation into whether the same antigens are overexpressed in IDH-mutant lower grade gliomas. It could be the case that some other combination of peptides would be more effective for lower grade gliomas than these ones.

    5. I think I already sent you this article some time ago, where they identified CSC in oligodendroglioma and some of the antigens which express "stemness"

      Single-cell RNA-seq supports a developmental
      hierarchy in human oligodendroglioma

    6. Yes this was a very good study, and the recent sequel was as well:
      Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq

      However none of the stemness genes identified in the Nature study are represented by ICT-107, which includes peptides derived from:

      AIM-2, MAGE-1, TRP-2, gp100, HER-2, and IL-13Ra2

      My point is that antigens common in GBM are not necessarily the same ones that would be found in lower grade IDH1 mutant gliomas, which have a rather different biology. For example, IDH-mutant glioma has a much lower average expression of IL-13Ra2 (one of the antigens targeted in ICT-107) than IDH wild type GBM. IDH1-mutant gliomas have a higher mRNA expression of some stemness markers such as SOX2, and lower expression of other stemness markers such as CD44, compared to GBM. I would be thrilled to see a peptide vaccine designed with low grade IDH-mutant gliomas in mind, but I suspect the actual peptides would be somewhat different compared to a vaccine designed for GBM.

    7. What about the clinical trials out of UCSF for low grade glioma right now?

    8. I wrote wrong...didn't mean to implicate that ICT-107 should be used for LGG, wanted to tell that this kind of approach that targets multiple antigens (especially stemness ones) can be successful.

    9. Oh, okay. Any opinions on IMA950? There is a current clinical trial combining it with Poly-ICLC and Varililumab.

    10. @ Maria,
      Starting with IMA950, one of the vaccines being tried in low grade gliomas at UCSF, the 11 peptides included in IMA950 were also selected based on GBM studies: "Approximately 30 samples from malignant tissue surgically removed from GBM patients were analyzed in a stepwise approach." "Genome-wide mRNA expression analysis by microarrays was used to identify genes over-expressed in GBM vs. a range of normal organs and tissues" " Identified TUMAPs (step 1) encoded by genes over-expressed in GBM (step 2) were considered TUMAP candidates suitable for the IMA950 vaccine"

      IMA950 use for low grade gliomas is essentially repurposing of a vaccine designed for GBM. While there is a chance this will work for some low grade gliomas, it would be more ideal to design a peptide vaccine specifically for IDH-mutant lower grade gliomas rather than repurpose vaccines designed for GBM. Still, it's difficult to predict how well this will work. IDH-mutant gliomas have especially high mRNA expression of BCAN, and one of the peptides in IMA950 is derived from BCAN (brevican).

      The other vaccine trial recruiting at UCSF for low grade glioma is a trial of GBM6-AD tumor lysate + PolyICLC. Again, it's hard to say how well this will work for lower grade glioma, as the cell line used as the source of lysate was a GBM cell line. However this cell line does express SOX2 which is abundantly expressed in low grade glioma.

      "GBM6 expresses many important DIPG antigens including IL-13Rα2, Epha2, and Her-2 (FIG. 1). Moreover, GBM6-AD also expresses key BTIC antigens including CD133, nestin, and Sox-2 (FIG. 1). Based on this data, the vaccination of GBM6-AD lysate targets the majority of DIPGs and GBMs that do not occur in other parts of the brain."

      Currently the only peptide vaccines specifically designed for IDH-mutant low grade glioma are the vaccines (in Germany and at Duke University) targeted the mutant form of IDH1. In my mind this peptide would be better off combined in a multi-peptide cocktail vaccine, so as not to select for the survival of cells that might randomly undergo deletion of the mutant IDH1 allele.

      Apart from off-the-shelf peptide vaccines, even personalized vaccines made from lysate from the patient's own tumor might not work well as single agents in lower grade gliomas, because of the immunosuppression caused by high levels of 2-hydroxyglutarate. This is a situation where mutant IDH1 inhibiting drugs (that would suppress the production of 2-HG) could be very useful in combination with a vaccine.

    11. I didn't mention my doctors names because may cause them to stop making offhand remarks about preliminary results.

    12. Thank you. Why do you suspect they are trying a peptide vaccine that will be less than ideal?

    13. I think because it is cheaper and faster to repurpose a GBM vaccine than develop a new one

    14. I agree with Matjaz that is likely the reason.

    15. Same reason that every new oncology drug approved for any type of cancer usually gets tested for GBM as well, even if it a less than an ideal candidate. I think these GBM vaccines have a better chance of working for low grade gliioma than most repurposed kinase inhibitors have working for GBM though.


    Has anyone read this? I can only open the abstract. It is from this month.

    1. This paper is just a news brief that summarizes the recent work of Ranjit Bindra et al. at Yale with PARP inhibitors for IDH mutant gliomas. I summarize the same work on this page under the heading "PARP inhibitors":

      I've uploaded the original study (Sulkowski et al) into a folder on the Google Drive libarary, which I've just shared with you. Find it in the "Pathology" folder -> IDH-mutant glioma subfolder -> Preclinical therapeutics sub-sub folder. I will also upload the Cancer Discovery new article there now.

  6. Hi Maria,

    I too have grade 2 oligo and actually unfortunately have a good friend who was also diagnosed with grade 3 oligo a few months after me. My tumor is fairly large and in my motor cortex and so not very operable, whereas my friend had an excellent surgery experience at UCSF and had full resection.

    So I would back up what others have said about surgery -- it has major benefits if near total resection or higher and it is very important to find the best surgeons. At UCSF they perform awake surgery, performed biopsy analysis on the fly during the single surgery, and adjusted their resection plan as they went based on the biopsy. Pretty amazing.

    The second big comment I would add is that its important to realize that the 'rules' of clinical trials are complicated. In general you can only get in a trial at initial presentation or at a new recurrence. Additionally many immuno therapy type trials also require presurgery done at their center. For instance both the UCSF trials you listed I tried to get into but because I had already started chemotherapy I was not eligible and they required surgery to be done at UCSF as part of the trial and my medical plan would not cover it. Furthermore during chemo there was discussion of using an off-label chemo drug (6-tg) but we decided against it because of the risk it posed of future trial exclusion because some trials exclude patients that have taken non standard of care treatments.

    So overall think about being strategic about what paths you choose when trying to
    leverage options for trials and whether or not to do chemo or RT, etc. On top of that, your N.O. often is the one who has to push to get consults and evals done to see if you would truly be accepted into a trial. So it can be fairly complicated, but can also be very promising. I agree with Matjaz and Stephen that there is big momentum towards major breakthroughs for oligo and other idh1 mut tumors. But it may take some careful planning to take advantage of those opportunities in this time frame.