The Case of Betty – Stage IV Colon Cancer
Betty was a 65 year old woman from BC, Canada whom was originally treated for stage IV metastatic colon cancer. Her doctors had tried the standard treatments for her disease including surgery, the chemotherapy protocols of FOLFIRI and FOLFOX, and the EGFR targeted drug pantimumumab.
However, Betty did not respond well to these standard protocols and a recent CT imaging scan that Betty’s oncologist had ordered showed that her disease was progressing.
Betty had endured surgery, multiple rounds of chemotherapy, and ineffective targeted drugs that left her with a multitude of side effects. Since her disease had not responded to standard treatments, her oncologist told her that they had run out of treatment options for her. She was told to get her affairs in order.
Betty wasn’t ready to just accept this and so she reached out to us.
How We Helped Betty Using Our 5-step System
- Introduced Advanced Diagnostics
Firstly, we obtained Betty’s medical records and discovered that she had recently participated in BCCA’s oncopanel pilot (TOP) study. This study uses advanced tumor DNA sequencing to identify mutations from a panel of cancer associated genes, with the aim of customizing patient treatments.
We immediately instructed Betty to obtain a copy of her oncopanel so we could determine if she had any targetable mutations. Since we did not know if Betty would be able to access the results from this study in a timely fashion, we also suggested that she contact a local company called Contextual Genomic’s, whom at the time was offering free access to their cancer hotspot mutational test, which also identifies cancer causing mutations.
Secondly, we asked Betty to contact an independent community oncologist near her home town that we had experience working with, and suggested that she get a PET-CT to establish the exact state of her disease.
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.
Betty’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.
Luckily, Betty was able to obtain her oncopanel tumor DNA sequencing results, which along with the results from her Contextual Genomics test, showed that she did not have the negative prognosis KRAS mutation.
Colon cancer patients with KRAS mutations typically do not respond well to standard treatments and the presence of this mutation would have also explained why she did not respond to the EGFR targeted drugs.
However, the tests showed that Betty did harbor a genetic mutation called the BRAF V600E mutation, which is commonly found as a driver of melanomas.
Betty’s colon cancer subtype
Current molecular and genetic testing allows the classification of colon cancers into four consensus molecular subtypes (CMSs), with distinguishing features and unique prognosis.
The CMS1 (microsatellite unstable/immune) subtype is defined as having a hyper-mutated and microsatellite unstable (MSI-High) genome. This subtype is known to create a strong immune response, resulting in a high amount of immune cells infiltrating the tumors.
Although this subtype commonly has a non-mutated or wild type (WT) KRAS gene, the combination of the BRAF V600E mutation and other key molecular features such as MSI and MMR of this subtype, results in a poor very poor prognosis.
Microsatellite (MSI) and mismatch repair MMR
To further confirm that Betty had the CMS1 colon cancer subtype, we ordered biopsy testing to look at the microsatellite (MSI) and DNA mismatch repair (MMR) status of her tumors.
Tumors that are MSI-High and/or MMR-deficient have a large amount of tumor DNA mutations because the DNA repair capabilities of these cells are damaged.
As we suspected, the tests showed that Betty’s tumors were both MSI-High and MMR-deficient, confirming that her disease was more than likely based on the CMS1 subtype, and that it had a high level of random DNA mutations.
Unfortunately, this combination of BRAF mutation, MSI-H, and MMR-D, results in the worst possible prognosis out of all of the colon cancers subtypes, and is largely resistant to known treatments.
In fact, recent studies showed that the median progression free survival (PFS) of BRAF mutated colon cancer patients was only 7.4 months, and the median overall survival (OS) was only 11.7 months with standard treatments. This compares poorly with BRAF-WT (non-mutated) patients, whom had a median PFS of 10.3 months and a median OS of 26.9 months.
Furthermore, the BRAF V600E makes cancers resistant to EGFR targeted drugs such as pantimumumab.
We are not sure why Betty’s BCCA oncologist continued to treat her with anti-EGFR drugs when the data from the TOP study should have indicated that the drug that would have little or no chance of working.
- Conducted Patient Specific Research
Based on the results of our analysis and identification of the CMS1 subtype, we reviewed the most recent gastrointestinal oncology symposiums for treatments that could specifically benefit Betty.
While the CMS1 subtype is known to have very poor survival rates and is very much treatment refractive, the high amount of mutations that results from the faulty DNA repair processes, also results in a tumor type that is highly immune-reactive.
In other words, the large amount of mutations in her tumors creates a tumor type that is easily recognized by the immune system because they look very different from the normal cells.
Unfortunately, although an active immune system is important for fighting most cancers and diseases, this specific type of tumor (CMS1), has the ability to hijack the immune system for its own benefits.
CMS1 tumors can hijack the immune system
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 the CMS1 colon cancer subtype, the tumors produce a high amount of a protein called programmed death one (PD-1).
The PD-1 ligand is a protein that every cell in the body is required to have on its outside surface. It acts much like a security card in that it tells the immune system that the cell is a normal body cell, so when the PD-1 ligand binds with the PD-1 receptors on the immune cells, it disables them. In these cases, the tumors have a blanket of PD-1 ligand surrounding them, allowing them to turn off the immune response.
This is one of three known mechanisms that tumors use to avoid detection by the immune system. The other two are known as the CTLA4, and IDO axis.
So why is this important?
Because Betty’s tumors have a high amount of mutations, they are able to initiate a massive response by the immune system in order to hijack its growth factors and resources, and then use mechanisms such as over expression of PD-1, CTLA4, and IDO to prevent getting attacked by these same immune cells.
The silver lining in this discovery is that a new class of drugs called immune checkpoint inhibitors are very beneficial for patients with immune-reactive tumors such as Betty’s CMS1 subtype.
In fact, we uncovered significant data showing that patients with this type of cancer responded very well to a specific immune checkpoint inhibitor called a PD-1 inhibitor. This drug acts like a sponge to remove the extra PD-1 ligand blankets that surround these tumors, which allows the immune cells to recognize the tumors as destructive and attack them.
Importantly, we found that one such drug called pembrolizumab is available in Canada and approved for melanoma and another such drug called nivolumab, is also available in Canada and approved for treatment of lung cancers.
- Interim Treatment Support
We immediately wrote up a patient report for Betty’s new treatment team, and her community oncologist prescribed off-label pembrolizumab via a local private infusion facility.
- Testing During Treatment
Since a mutated gene is unlikely to get fixed during the course of disease, and since we knew that ALL of Betty’s tumors carried the BRAF V600E mutation, we used a blood based liquid biopsy test to assess the level of BRAF V600E mutations in her blood.
This liquid biopsy detects circulating tumor DNA (ctDNA), and measures 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 her 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 than other methods such as radiographic imaging and other non-specific blood-based tumor markers such as CEA and 19-9, which are used by the public medical system. Plus, patients are not subjected to ionizing radiation as with CT and PET-CT scans.
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.
The liquid biopsy test we performed immediately before her initial treatment with pembrolizumab, showed that Betty had very high level of the BRAF V600E mutations in her blood (28.1%), indicating that her disease was growing rapidly.
- Clinical Trial Support and Advocacy
At the time of this report, Betty has had 4th infusions of pembrolizumab, and a recent PET-CT showed that the majority of her tumors had significantly lower SUV levels, indicating tumors that they are dying and responding to the drug. Additionally, some of her tumors have already shrunken.
However, her doctor was alarmed at what appeared to be some new growths, based on very low non-specific SUV levels in certain parts of her liver. 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 pembrolizumab removes the excess PD-1 cloak surrounding tumors, the immune T-cells start to recognize them as actual tumors and infiltrate (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, but which can now be seen because of the immune cells entering the tumors.
Furthermore, with pembrolizumab, not all of the body’s tumors will respond at the same time. In fact, we have seen more than a few cases were a patient was put on a PD-1 inhibitor drug during early clinical trials years ago, but was removed after only a few treatments because the imaging showed increased tumor sizes in the patients.
However, years later these same non-responding patients were shown to have responses to the drugs, and are still cancer free many years after they were initially treated. This is referred to as “delayed response”.
It is estimated that up to 30% of patients treated with these drugs will have pseudo-progression and/or delayed responses.
To our knowledge, the liquid biopsy is the best way to determine if pseudo-progression is occurring. Based on the possibility of a delayed response to the drug, we are waiting for a few months before ordering a follow up liquid biopsy.
Recently, we uncovered exciting new evidence on a new drug combination that showed a specific benefit for colon cancer patients that have the same features (MSI-H, MMR-D, BRAF V600E, and WT-KRAS status), that Betty has.
In this group of patients, when pembrolizumab was combined with another checkpoint inhibitor (CTLA4 inhibitor), the patients experienced significant increases in responses, disease control, and overall disease-free and survival rates compared to pembrolizumab alone.
We immediately contacted Betty’s treatment team to educate them on this new protocol, and after being convinced by the overwhelming data, her prescribing oncologist added the CTLA4 inhibitor ipilumumab to her treatment protocol.
Furthermore, if these drugs stop working, she has a variety of other targeted therapies that have the potential of providing her with more time, without the damaging side effects of standard chemotherapy.
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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