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Damian is a 54-year-old man from British Columbia, Canada, who was originally treated for stage III metastatic colon cancer. Because his surgery found 17 out of 22 lymph nodes were positive for cancer, his doctor suggested that he follow up with the chemotherapy protocol CAPOX.
His doctors also noted a suspicious nodule in his liver, and provided him with a CT scan and an MRI. Unfortunately, these scans were inconclusive.
Given the risk of recurrence with the standard treatment, Damian’s doctor suggested that he reach out to CTOAM for a second opinion. We were able to help Damian and his treatment team access advanced diagnostics not yet available through the public medical system.
Firstly, since Damian had just finished surgery and we wanted to ensure that the liver spots were not metastasis, we arranged for him to get a PET/CT at a private US clinic.
PET/CT, unlike other forms of medical imaging, is able to identify active tumours at a very small size, based on the biological activity of the tumour.
While most forms of imaging look at the density of the tumour and compare it to the surrounding tissues, PET/CT uses a harmless radioactive isotope that is bound to a sugar molecule.
Since tumour cells are constantly growing and therefore highly metabolic, they drink up more of the sugar-isotope solution than the surrounding tissues, and any tumour will glow like a Christmas tree light.
Since only live tumours will drink the sugar-isotope solution, PET/CT can tell if a tumour 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 tumour drinks depends on how fast it is growing, a PET/CT can determine how aggressive a specific tumour is compared with other tumours in the body.
This can allow doctors to focus surgery and treatments on the tumours that are most likely to metastasize.
Damian’s PET/CT revealed numerous metastatic sites, and also provided us with a baseline SUV reading for each tumour. This means that we’ll be able to use future PET/CTs to confirm if his tumours are responding to treatment or not.
Luckily, the PET/CT did not find any active sites of metastasis, so Damian continued his CAPOX regimen.
Secondly, we obtained a sample of Damian’s tumours and sent it for tumour DNA sequencing. This test looks for a variety of mutation in potentially targetable tumour DNA genes.
Unfortunately, one of the mutations we found, referred to as NRAS G12V, was a negative prognostic feature, and patients with this mutation have a poor prognosis.
Further, this mutation also prevents benefits from the use of the FDA approved EGFR targeted drugs, and anti-angiogenesis drugs such as avastin, which can both be very effective in treating colon cancers.
In other words, this specific genetic mutation results in a very aggressive and highly metastatic form of colon cancer that is unlikely to respond to most standard therapies for very long, and we predicted a likely survival time of a few years from the time of his initial diagnosis.
We then conducted research on the latest data regarding colon cancers with NRAS mutations.
Current molecular and genetic testing allows the classification of colon cancers into four consensus molecular subtypes (CMSs), with distinguishing features and unique prognosis. The CMS3 (metabolic) subtype is defined as having deregulated metabolic system and a high occurrence of KRAS and NRAS activating mutations.
While this subtype tends to respond well initially to chemotherapy, it typically returns in a highly aggressive and treatment-refractory manner which is resistant to known standard therapies such as FOLFOX and FOLFIRI.
Additionally, there are no drugs currently available to target RAS-based signalling. Based on the results of our analysis and identification of the CMS3 subtype, we reviewed the most recent gastrointestinal oncology symposiums for treatments that could specifically benefit Damian.
Interestingly, we found that diet and exercise had a strong role in reducing the growth potential of this specific metabolic based tumour, so we created a tumour-fighting diet and exercise plan for Damian, which he followed faithfully.
During his chemotherapy, a new form of testing was created which allowed us to measure the amount of NRAS – mutated tumour cells in his body using a simple blood test. It allowed us to look at the actual amount of cancer cells in his body.
It works like this: Since a mutated gene is unlikely to get fixed during the course of disease, and since we knew that ALL of Damian’s tumours carried the NRAS mutation, we used a blood based liquid biopsy test to assess the level of NRAS mutations in his blood.
This liquid biopsy detects circulating tumour DNA (ctDNA), and measures the ratio of the mutated NRAS (cancer cells) to the non-mutated NRAS (normal cells) genes in order to provide us with a rough idea of the actual amount of cancer cells in his body at a given time.
Testing all of the body’s tumours at the same time using liquid biopsies is a much more accurate way of determining responses to treatments than other methods, such as radiographic imaging, and other non-specific blood-based tumour 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.
Looking at a complete body-wide drug induced anti-tumour response is essential for determining how well the treatment is working.
The liquid biopsy test did not find any evidence of active disease, and Damian went on with his life.
Unfortunately, 8 months later, Damian’s blood work started to show an increase in his tumour markers, and the PET/CT ordered by his oncologist showed an aggressive tumour in his liver. Damian was sent for surgery and the liver tumour was removed. We immediately reviewed the latest data and found that there was a slight benefit for post-operative chemotherapy when patients with the CMS3 subtypes had a liver metastasis.
Although the public medical system initially refused to cover the cost of his post-operative chemo, they decided to allow it based on the new data that we presented to them.
We also uncovered some data that indicated that a certain drug used to treat acid reflux could potentially slow the return of his cancer, so Damian obtained a prescription for the drug and started taking it.
Since this new liver tumour was very aggressive, we decided to sequence the tumour DNA using a newer and more advanced test that looks at many more genes.
The results from Damian’s second tumour DNA sequencing showed that he had quite a few new mutations that were driving his cancer to grow and metastasize, including a total of 13 previously unknown mutations that were unique to him.
Damian recovered well from his surgery and remained cancer free for another 8 months. However, once again, Damian’s tumour markers started to increase, so we arranged for a private PET/CT from a local clinic that we work with called Premier Diagnostic Center. This clinic is our first choice for PET/CTs because we get results very quickly, it is one of the lowest costing scans we know of, and the radiologist reports the SUV values of EVERY tumour, unlike many other clinics we have dealt with.
Unfortunately the PET/CT showed that Damian’s cancer had returned with a vengeance and he had multiple sites of metastasis. His oncologist informed him that he would be lucky to survive the next few months.
We immediately ordered an MMR test and a PD-1L ctRNA test to see if Damian would be a candidate for anti-PD-1 immunotherapy. We also ordered a HER2 test to see if Damian would respond to anti-HER2 drugs such as Herceptin.
Unfortunately, all three tests came back as negative.
After reviewing the latest gastrointestinal conferences, we found that a new drug called TAS-102 (Lonsurf) was providing benefits to patients with advanced KRAS mutated colon cancers and would provide Damian with the potential of another 1-2 years survival at best.
However, this drug was not available in Canada. We contacted the distributor of the drug and arranged a deal where Damian’s Canadian oncologist was able to prescribe the drug, and the distributor would ship it to a USA pharmacy close to the Canadian border where Damian could travel to get this drug, at a cost of $12,000 per month!
Prior to starting this drug, we performed a ctDNA NRAS test to act as a baseline so we could ensure that this expensive drug was actually working. We were shocked to see that the levels of his NRAS positive cancers cells had risen to 6.45% in only a few months.
After one month on TAS-102, we performed another ctDNA NRAS test and were happy to see that Damian’s level was down to 1.38%! However, his basic tumour markers ordered by his public system oncologist had risen substantially, and his oncologist took him off the drug.
This was obviously a great concern for us, so we took steps to ensure that Damian’s oncologist was aware of how TAS-102 works.
First, we reviewed the blood tests ordered by his oncologist and realized that this oncologist was making his comparisons from blood work done many months before the actual spike in tumour activity, and importantly, that there were no blood test results from immediately prior to taking the TAS-102 to compare with.
Additionally, we reviewed the latest data on TAS-102 responses and found that when the drug produced neutropenia (low neutrophils) in patients within the first month of taking it, those patients went on to have significant responses compared with other patients that did not get neutropenia within the first month.
In these patients, the TAS-102 is not broken down as quickly as with other patients, so the neutropenia is an indicator that the person has a higher absorption of the drug and will therefore have a better response to it. Damian HAD experienced neutropenia within his first month on TAS-102.
We also found evidence that showed a brief but radical spike in general tumour markers immediately after finishing the 21 day cycle of TAS-102.
We immediately forwarded this data to Damian’s oncologist, who reluctantly put Damian back on TAS-102 for another two cycles.
By this time, we had gathered new research showing that when patients with KRAS mutated colon cancers were given a drug called a MEK inhibitor, these patients responded to PD-1 inhibitors. Although patients with KRAS mutations do not typically respond to PD-1 inhibitors, taking the MEK inhibitor causes a spike in signalling pathways that can stimulate an immune response.
We also had the prior knowledge that Damian’s last tumour DNA sequencing test showed a high level of mutation, indicating a immunogenic phenotype, which was unique to his case.
Since the TAS-102 also caused a spike in tumour markers, and since Damian was about to finish his 3rdcycle of TAS-102, we theorized that if Damian was given a MEK inhibitor plus PD-1 inhibitor combination immediately after finishing his TAS-102 (while his tumour markers were still high), then his tumours would have the best chance of responding to this immunotherapy.
Pembrolizumab and Trametinib
We presented this new plan to Damian and his treatment team and although reluctant due to the heavy cost of these two drugs (reaching more than $20,000 per month), they agreed to try one cycle.
First, Damian was put on a single one month trial of the PD-1 inhibitor pembrolizumab. Amazingly, within the first month, Damian’s tumour markers started to fall.
Since we knew that an immediate drop in tumour markers after treatment with PD-1 inhibitors indicated a response, we urged his treatment team to continue with a second cycle.
A month later, his tumour markers had dropped even further, and we were able to convince his team to add the MEK inhibitor trametinib.
5. Patient Outcome
It has been 3.5 months since Damian has been on this new combination and to date, his tumour markers have gone from 286 – 162 (AP), 295 – 137 (GT), 140 – 60 (CD19-9), and 160 – 81 (CEA), indicating a significant response.
Importantly, when patients respond to PD-1 inhibitors, the responses are very durable, and we have seen many cases where after only 2-3 treatments, the tumours never come back. We will be performing further tests including ctDNA and PET/CT in the near future to confirm this response, but for now, Damian claims he has not felt better since the onset of his disease.
Unfortunately Damian’s cancer has recently stopped responding to the pembrolizumab, and he has started on a course of irinotecan, capecitabine, and avastin, which we hope will provide him with more time.
Based on our previous research, we determined that Damian would more than likely respond to this triplet combination as it targeted the redundant signaling pathways. While Damian’s oncology team was skeptical, they agreed to try this new combination, even though Damian had not responded significantly to these same drugs when used previously.
Additionally, from our experience, patients tend to respond to chemotherapy agents and other targeted agents that they had previously become resistant to after treatment with immune checkpoint inhibitors such as pembrolizumab.
Great news! Damian has responded very well to the triplet drug combination and his CEA and 19-9 tumour markers have gone from 751 to 152, and 105 to 55 for CEA and 19-9 respectively. Furthermore, Damian reports feeling much better than he has in a while.
And finally, his attending oncologist reported that his previous tumours have shrunk, and a remaining 2 cm lymph node tumour in his axilia will be removed surgically. Great news for Damian.
More exciting news! A recent blood test revealed that Damian’s CEA and 19-9 tumour markers have gone from 751 to 50, and 105 to 59 for CEA and 19-9, respectively.
Additionally, recent data is showing improved results with the antibody-drug conjugate labetuzumab govitecan, which combines irinotecan with an antibody for CEACAM5.
CEACAM5 is a cell surface glycoprotein that plays a role in cell adhesion, as well as in intracellular signaling, which is commonly over-expressed in colon cancers. In this study, nearly 40 percent of cancer patients saw reduction in both tumour and plasma carcinoembryonic antigen level. The median progression-free survival was 3.6 months and overall survival 6.9 months.
We will be looking into this drug as a future treatment option for Damian if/when his cancer progresses.
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 precision oncology specialists, doctors, and patient advocates can make all the difference in the outcome of your disease.
If you or a loved one has cancer, contact us today so we can do a brief review of your medical records. CTOAM’s cancer experts will ensure that you have access to the most advanced tests and treatments available for your unique form of cancer – as close to home as possible.
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