The Case of Joan – Stage IV Melanoma
Joan was a 45 year-old woman with stage IV metastatic melanoma. At the time, there was a new targeted trial with a drug that targeted a key mutation called BRAF V600E. Her oncologist ordered the standard immunohistochemical (IHC) testing of her biopsy sample and determined that her tumors were BRAF mutation negative, and that she would not be a candidate for anti-BRAF therapies.
She was given the option of standard dacarbazine chemotherapy, which has been reported to provide a 2.5-month progression free rate and a 10.7-month median overall survival advantage. Since her disease would not respond to standard treatments, her oncologist told her that they had no other treatment options for her. She was told to get her affairs in order.
Joan wasn’t ready to just accept this and so she reached out to us.
How we helped Joan using our 5 step system
1. Introduced advanced diagnostics
Firstly, we recommended a pre-treatment PET-CT to establish the exact extent of her disease and suggested a local private clinic called Premier Diagnostics that we had worked with and which was currently offering the best price for a full body private PET-CT.
PET-CT, which unlike other forms of medical imaging, is able to identify active tumors at a very small size, based on the biological activity of the tumor.
While most forms of imaging look at the density of the tumor and compare it to the surrounding tissues, PET-CT uses a harmless radioactive isotope that is bound to a sugar molecule.
Since tumor cells are constantly growing and therefore highly metabolic, they drink up more of the sugar-isotope solution than the surrounding tissues and any tumors will glow like Christmas tree lights.
Importantly, since only live tumors will drink the sugar-isotope solution, PET-CT can tell if a tumor is alive or if it has been affected (killed) by a specific treatment. No other form of imaging can reveal this essential information!
Furthermore, since the amount of the sugar-isotope solution a specific tumor drinks depends on how fast it is growing, a PET-CT can determine how aggressive a specific tumor is compared with other tumors in the body. This is referred to as the serum uptake value (SUV), and allow doctors to focus on the tumors that are most likely to metastasize.
Joan’s PET-CT revealed numerous metastatic sites, and also provided us with a baseline SUV reading for each tumor so we will be able to use future PET-CTs to confirm if her tumors are responding to treatment or not.
2. Personalized Research
Secondly, we obtained a sample of Joan’s tumor tissue and sent it for tumor DNA sequencing. We looked for cancer causing mutations in the DNA of over 340 genes involved in melanomas and other cancers.
Unfortunately at the time, the tumor DNA sequencing panel was not as advanced as it is today and the turn-around time for this assay was over 3 months.
3. Clinical Trial Research and Support
In order to provide Joan with an interim treatment solution, we researched the latest peer-reviewed data and oncology conferences for advances in treatment of metastatic melanomas.
Interestingly, our research turned up some very significant data on new drugs that target two arms of the immune system known as CTLA4 and PD-1.
A word on CTLA4
The cytotoxic T-lymphocyte-associated protein 4 (CTLA4) is a receptor that functions to downregulate immune responses so that the immune system does not attack and target healthy cells.
To summarize, when the immune system sends T-cells to investigate a foreign object or tumor, they surround it and then create an immune response that causes the activation of different arms of the immune system.
The immune cells do this by releasing a multitude of growth factors and resources that are required for a rapid expansion of the immune system and a proper immune response. However, these growth factors and resources can also be hijacked by the tumors, allowing them to grow rapidly and metastasize.
In some cancers such as melanomas, the tumors produce a high amount of the CTLA4 protein, causing the tumors to be protected and hidden from the immune system.
This is one of three known mechanisms that tumors use to avoid detection by the immune system. The other two are known as the PD-1, and IDO axis.
We reached out to a local oncologist whom was instrumental in recently bringing a new CTLA4 inhibitor to British Columbia called ipilumumab. Unfortunately, this oncologist was not having a lot of luck with ipilumumab, so we researched the latest clinical data regarding administration of this new drug.
Our research uncovered important new data showing that not only was the current dosage of 3mg/kg ineffective, but that significantly improved results could be obtained by combining a steroid called budesonide, and another medication called GM-CSF, which was commonly used to stimulate the production of white blood cells in patients with neutropenia (low neutophils) that were undergoing chemotherapy.
For the interim treatment, we recommended the 10mg/kg dose of ipilumumab (standard was 3mg), combined with budesonide and GM-CSF.
We also suggested that Joan’s oncologists look into obtaining future access to the newer, yet to be named drug that targeted the PD-1 axis as the pre-clinical data was very impressive.
To our delight, many of Joan’s tumors responded very quickly to this unique combination of drugs.
4. Genetic Testing During Treatment
During the course of her therapy, the tumor DNA sequencing results of her biopsy identified a BRAF V600E mutation, which was missed by her initial pathologist at BCCA.
This new information was important to us because it opened up two new opportunities to help Joan;
- A new drug that targeted BRAF V600E mutations called vemurafenib was providing significant benefits to patients with BRAF-mutated melanomas and had recently been approved by the FDA.
- Since a mutated gene is unlikely to get fixed during the course of disease, and since we now knew that ALL of Joan’s tumors carried the BRAF V600E mutation, we could use a blood based liquid biopsy test to assess the level of BRAF V600E mutations in her blood in order to determine how she was responding to the drug.
A word on liquid biopsies
Liquid biopsies detect circulating tumor DNA (ctDNA), and measure the ratio of the mutated (BRAF) to the non-mutated (BRAF) genes, in order to provide us with a rough idea of the actual amount of cancer cells in a body at a given time.
Testing all of the body’s tumors at the same time using liquid biopsies is much more accurate way of determining responses to immune checkpoint inhibitors such as CTLA4 than other methods, such as radiographic imaging and other non-specific blood-based tumor markers such as CEA, and CD19-9/ 15-3, which are used by the public medical system.
This is because different tumors interact with the immune system at different stages of the disease. Looking at a complete body-wide drug induced anti-tumor response is essential for determining how well the treatment is working.
Importantly, patients are not subjected to ionizing radiation as with CT and PET-CT scans.
Using liquid biopsies to determine an immune response
A mid-treatment PET-CT showed mixed results with the majority of her tumors showing significantly lower SUV levels (indicates tumors that they are dying and responding to the drug), with some of her tumors having already shrunken.
However, her doctor were alarmed at what appeared to be some new growths, based on very low, non-specific SUV levels in certain parts of her body. Based on the RECIST response criteria, this finding would indicate what is known as a “mixed response”, and that the drug is not working as well as we had hoped for.
We explained to her treatment team that this “mixed response” was based on the mechanics of the drug, and is referred to as pseudo-progression. Since ipilumumab removes the excess CTLA4 cloak surrounding tumors, the immune T-cells start to recognize them as actual tumors and infiltrate that enter the tumor cells in order to break them down.
This infiltration of the immune cells into the actual tumor results in a tumor that is much larger than it was previously was, and since there is activity inside of it from the T-cells attacking the tumors (immune response), it would show some very low SUV levels from a PET-CT scan.
In other words, there were likely many small microscopic tumors throughout Betty’s body that were too small to be detected previously via PET-CT, but which can now be seen because of the immune cells entering the tumors making them large enough to be detected.
In order to determine if the mixed response was due to immune infiltrates rather than disease progression, we performed a ctDNA assay, which showed no presence of the BRAF V600E mutation, indicating pseudo-progression as the cause of the mixed PET-CT results in the majority of her tumors.
5. Clinical Trial Support and Advocacy
With all of the amazing new advances in cancer diagnostics and treatment, our work at CTOAM is never boring and this case was just another example of the benefits of real-time treatment information!
In a fascinating turn of event, just as Joan was ending her ipilumumab treatments, her community oncologist, the one instrumental in bringing ipilumumab to British Columbia, was able to provide her with access to a new PD-1R inhibitor called pembrolizumab, via clinical trial by distance.
However, only patients that did not have a BRAF V600E mutation were allowed access to this trial because if they had this mutation, then they could be treated with vemurafenib.
This presented us with a real dilemma!
Do we share our new found knowledge of her BRAF mutation with her treatment team and the medical system, resulting in her not being able to enter the pembrolizumab trial, or do we withhold this information so she can enter the trial?
Once again, we hit the books and uncovered and did an extensive review on both vemurafenib and pembrolizumab.
We uncovered newly published trial data showing pembrolizumab was vastly superior to any known treatment of melanomas, and with minimal side effects.
Furthermore, melanoma patients that took both ipilumumab and pembrolizumab had some of the most drastic responses ever to be recorded in the history of melanoma treatment.
This was a no brainer, we suggested that Joan enter the pembrolizumab trial and only release the BRAF mutation data to her treatment team IF the pembrolizumab was not effective, as then she could go on to vemurafenib.
With further research and consultation with her oncologist, Joan was provided with experimental access to the PD-1R inhibitor pembrolizumab.
New data is showing exceptionally long term survival rates for many melanoma patients that have taken both ipilumumab and pembrolizumab and a recent PET-CT failed to find any evidence of her disease. Currently, Joan remains cancer free, well over 2 years after initiating her treatments.
Should her disease recur, we can resort to anti-BRAF therapy, as well as the amazing next generation PD-1 ligand inhibitors, which are showing improved benefits to that of the first generation PD-1 receptor inhibitors such as pembrolizumab.
As you can see, CTOAM’s advanced diagnostics , records review and consultations can result in significant benefits to a patient’s outcome. Having access to a team of knowledgeable scientists, doctors and patient advocates that WORK FOR YOU and NOT THE MEDICAL SYSTEM, can make all the difference in the outcome of your disease!
If you or a loved one is fighting cancer, give us a call so we can do a brief review of your medical records. It is important to be sure that you KNOW that you are doing all you can, and that you have access to the best treatments for your own unique case.
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