TMZ Hypermutation in LGG (Low Grade Glioma)

I’ve been meaning to write about this issue for several months, and apologize for the delay in sharing. I was overwhelmed by the magnitude of the report, and didn’t know how to broach it. This is by far one of the most important research studies I've ever read regarding low grade glioma. Finally, some legitimate information which should help patients decide on treatments. I have sent the papers to my tumor friends that I know are considering, or on TMZ, of the hypermutation issue, and now I know that a post has to be written for those out there on the interwebs looking for direction on whether or not to take temozolomide (TMZ) for a low grade glioma. I’m going to embed the research study, along with the supplement, and although I realize not many are interested in reading the entire report (which is actually only three pages of reading), I’m providing a few teasers so that you can either get the gist of it, or it may even entice you into reading the whole thing. Just as an aside, if I know you already took TMZ for your low grade glioma, I did not send the documents to you. I went back and forth on whether I should say something, or not, and I decided it would only be harmful, and scary. If you've already taken it, there's nothing you can do. And ultimately, most likely, if you are a hypermutator, you would have found out with a recurrence during or around treatment. 

Mutational Analysis Reveals the Origin and Therapy-Driven Evolution of Recurrent Glioma 

(TMZ Hypermutation of grade 2 glioma induced into GBM)

“Beyond maximal, safe, surgical resection, there is currently no standard of care for patients with low-grade glioma, and options include surveillance, adjuvant radiation alone, TMZ alone, or radiation and TMZ.”

"While the initial tumors and most of the recurrent tumors in our cohort had 0.2-4.5 mutations per megabase (Mb) (21, 22), six of the ten patients treated with TMZ had recurrent tumors that were hypermutated; that is, they harbored 31.9-90.9 mutations per Mb (table S6).”

"The introduction of thousands of de novo mutations may drive the evolution of TMZ-resistant glioma cells to higher states of malignant potential (1, 23). Indeed, all six recurrent tumors that showed evidence of TMZ-induced hypermutation underwent malignant progression to GBM, a high-grade tumor with a worse prognosis (8, 9).”

"We also demonstrated an alternative evolutionary path of low-grade glioma that is largely determined by adjuvant chemotherapy with TMZ.”

“Mutation rates in each tumor pair suggested that >98.7% are due to TMZ-induced mutagenesis (10).”

"There is currently no information on whether treatment of grade II astrocytomas with TMZ confers longer overall survival (8)."

"Future basic and clinical studies must weigh the initial antitumor effects of TMZ against the potential risk of inducing new driver mutations and malignant progression.”

What I see, that is lacking in our medical system, is a complete disconnect between current research and general practice. I’d like to think that doctors want us to survive, that they prescribe treatments to prolong our lives, but the fact remains that the current system is antiquated, and dangerous. It’s dangerous because there is tons of research being done, but doctors are not aware of the changes, and new developments. When a study like this comes out, every nerco-oncologist in the world should be aware, and changes in treatment recommendations should be adjusted accordingly. People are dying because of this lack of knowledge. It’s unacceptable. 

We are not receiving “best practice” we are receiving “marginal, outdated practice”. I recognize that doctors are busy, that they have massive workloads, and we can’t expect them to be up on all the latest research (or can we) but this is our lives, we need the most cutting edge information. It is my opinion that before neuro-oncologists prescribe TMZ alone (or even in combination with radiation) low grade patients should be apprised of the serious risks of taking TMZ. That using it alone (on low grade glioma specifically) has shown a 60% chance of causing a recurrence that will present as a GBM. That is a horrendous risk. It’s well known that brain tumors recur and recur and recur until it progresses to the point where it kills you, but usually with low grades (left untreated by TMZ or radiation) it most often recurs as the same low grade. At least for the first few tumor recurrences. Living a life with a glioma is a chess game. It’s always a guessing game about when to treat and what treatment to use. You don’t want to “poke the beast” with the wrong treatments, yet you often aren’t comfortable with the standard wait and watch protocol. 

It is imperative that patients know the dangers of TMZ with low grade glioma so that they can make educated decisions. That’s why I’m writing this blog post. I hope it helps spread the word that treatment with TMZ for low grade glioma has inherent danger.

Want to know what my buddy Stephen from Astrocytoma Options says? 

"As the hypermutation phenotype has been seen in some grade II astrocytomas and also in glioblastoma (14) following TMZ therapy, by extrapolation it is likely that it also occurs in grade III astrocytoma patients. The frequency of this occurrence will not be known until larger studies are completed. This new knowledge should have immediate impacts on chemotherapeutic strategies, especially for lower grade glioma." 

One of the many things I appreciate about Astrocytoma Options is that Stephen has a way of digesting information and using it to our advantage. What I'm saying in this blog post, is not that we should throw out TMZ, but that we need to better understand it's benefits and downfalls. It may still be a benefit in a cocktail approach, but needs to chosen with care. 

"If a decision is made to proceed with TMZ chemotherapy for lower grade (II and III) glioma patients in the adjuvant setting (post-radiation) or in the absence of radiation, one strategy to reduce the risk of TMZ-induced hypermutation could be to apply a combination strategy, involving a simultaneous or alternating application of other cytotoxic drugs, which reduce the evolutionary selective pressure exerted by TMZ alone."

I hope this information lives on in the interwebs, the information must get out, and it seems as if we have to change the way we are treated, literally, by informing our oncologists.

Does Altruism Exist?

I'm sitting at the JFK waiting to fly back home and wondering to myself how I got so fortunate in life. I just spent the night (as I usually do) with my friends Nate and Miraim, and baby Sol of course, and just being around them is calming, and fun, we talk about everything. It's engaging and energizing, and refreshing, and fills me with joy. Flash to today where Sol, Miriam and I met up with our friend John (Steph was stuck at work) for lunch and again it's the most invigorating, expressive, comprehensive friendship. How did I get so lucky to live this life and be surrounded by such amazing humans? These beautiful souls who think deeply, whose hearts are profoundly touched by human suffering or the human cause. I think they all see themselves as just normal people, but I see them as the glue that keeps humanity real, and kind. I hear their words, as they talk on any subject, and they care. They have such huge hearts, it's the most lovely thing.

The shot went well, fabulously well, Dr Germany said something along the lines of, "We're on a winning team" in reference to my protocol. Man that's a fantastic thing to hear. I don't know why I get to live this - I don't even have a good word for it - blessed life, but I am grateful for every second. And along with living a life that is true to me, and my evolving views, I will also continue my mission to help other tumor patients achieve health, and longevity.

The bandaid peaking out reminds me of today's life giving treatment

The thought has crossed my mind that now I'm stable, I could say screw it and just go live my life (while obviously continuing my treatments). I could stop blogging. I could unconnect from social media and just garden, or find a career that could withstand my seizures, and time off to travel for treatments. I could turn my back on the brain tumor world and focus on anything, or everything, else. I could just spend my time in an unrelated field, or focus on other endeavors, but the truth is that I feel the need to pay it forward. I am driven, compelled, to help others who are just starting their journey, or perhaps are dealing with a relapse/recurrence. I could not turn my back on family, and that's who you all are. You are my brain tumor family, and I will not abandon you. It would be easier, probably, and less emotional, less stressful, but who would I be if I didn't help those in need? It's not the kind of person I want to be. We all have choices every moment of every day about who we are and how we're going to live our lives. I have somehow navigated my way through this crazy diagnosis, and although I'm not guaranteed tumor stability for life, with this path that I'm on, it's working for now and I know I can help others. I've done it and will happily continue. It's actually even selfish sometimes because it makes me feel good when I talk to another brain tumor diagnosees and help them figure out their own plan, because everyone is different. Each brain tumor patient can blaze their own path; they can take little bits here, and little bits there, from other patients who have been successful. When I see, or hear in their voice, the determination to live, it fuels me. When I share what I know, or connect them with others who can also give valuable information, I feel intrinsically good. Is there such a thing as altruism? I really don't know.

So, even though I worry about you guys, all my tumor friends, crying for you at times, I wouldn't change a thing about the responsibility to help. I know this is a choice. I see pieces of myself in you, I know your struggles, I know your fears. Know that I'm here, and I will help you in any way I can.