41-year-old Korey, an engineer, had been suffering with a dry cough for some time – and, in late 2015, he was diagnosed with carcinoma of the lung. A follow-up PET-CT then identified multiple masses in the liver. And later, a liver biopsy (in March 2016) resulted in a diagnosis of stage IV metastatic well-differentiated neuroendocrine carcinoma.
In June of that year, Korey sought a second opinion from a private medical company and the hired expert confirmed the dire diagnosis. Given the diagnosis, Korey started on monthly Lanreotide, an indicated drug that targets neuroendocrine tumor cells. In December 2016, Korey started taking palliative Capecitabine plus Temozolomide. Fortunately, after experiencing a significant response to this chemotherapy combination, Korey was able to get on with his life.
All was well for Korey until 2018 when he started experiencing pain in his hip. After some more tests and imaging, Korey received the dreadful news that his cancer had come back.
In November 2018, a more extensive pathology work-up concluded that not only did he have a recurrence, but the tumor was a combination of two different types of cancer, with part of the tumor being a high-grade neuroendocrine carcinoma and the other part being an undifferentiated large cell carcinoma. This is considered a worst-case scenario.
Being a young, healthy man with a family, Korey realized that the complexity of this new diagnosis required a different approach from standard care. And so, in early 2019, he reached out to CTOAM to see if we could help.
When we first reviewed Korey’s medical records, we were disappointed to see that none of his previous doctors had considered any precision oncology tools – and that the genetic and molecular make-up of his disease had never been investigated!
Since Korey was young, had a healthy lifestyle, and had children to consider, we ordered an inherited germline test for Korey. This test looks at Korey’s non-tumor cells in order to identify any mutations in genes associated with cancer. And it allowed us to see if Korey had a predisposition to developing cancer that may be passed on to his children.
The results of Korey’s germline sequencing showed that, as expected, Korey had 4 inherited mutations involved in cancer-causing genes. The first mutation was pathogenic and in a gene involved in repairing damaged DNA. This was the obvious cause of his cancer.
Additionally, there were 3 other mutations that were classified as variable of unknown significance (VUSs). VUSs are mutations in cancer-causing genes, but the exact mutations have not yet been researched. We performed our own specialized artificial intelligence (AI) computer-based modelling on these mutations and found that they were also pathogenic (cancer-causing).
Importantly, all 4 genes were known to occur in both of the cancer subtypes that Korey had been diagnosed with. This meant that both of these separate subtypes of cancers would respond to the same treatments – an important consideration for future treatments.
Tumor DNA sequencing
In order to determine specific personalized treatment options, we immediately ordered a tumor DNA sequencing panel for Korey. We decided on the Foundation One CDX, because it’s one of the only FDA approved sequencing panels, which is an important consideration given that we wanted to consider all options, including off label drugs and clinical trials.
Importantly, this test also looks at changes in microsatellite instability (MSI) and damage to genes involved in mismatch repair (MMR). It also determines the amount of mutations per million base pairs of DNA. These additional tests are important because they can indicate whether immune checkpoint inhibitors could play a role in Korey’s treatment.
By mid-January, we received the test results back from Korey’s sequencing tests.
When we reviewed the tumor DNA sequencing results, we were shocked to find that Korey had the highest amount of mutations we had ever seen (209 mutations per million base pairs of DNA). This condition refers to high tumor mutation burden (TMB). TMB occurs when there are mutations in the genes involved in repairing damaged DNA.
Because these genes are not functioning, Korey’s cells were unable to repair the common mutations that occur on a daily basis and the result was a massive buildup of mutations involved in most of the cancer associated genes. This can result in a very aggressive type of cancer that grows quickly; is resistant to standard chemotherapy; and typically results in cancer occurring at a very young age.
However, it also has the consequence of creating a subtype of cancer that looks very different to the immune system than Korey’s normal cells – and, because of this, it can be very effectively treated (and even cured in some cases) by a class of drugs known as immune checkpoint inhibitors.
A second benefit for Korey was that since he had so many cancer-causing mutations, we had a good list of potential targeted drugs to consider if immunotherapy didn’t work.
Immune Checkpoint Inhibitors
Currently, there are two types of these drugs available: Programed death one (PD-1L/R) inhibitors and CTLA4 inhibitors. CTOAM has a lot of experience with immune checkpoint inhibitors and we spend a lot of research time identifying molecular features that determine if these drugs will work. In fact, we were the first company in Canada to use a PD-1 inhibitor on a patient! Incredibly, this patient – who was given just months to live at the time by her doctor – is now still completely cancer free, 5 years later.
So we suggested that Korey try a drug that was readily available in Canada called Pembrolizumab. In short, this drug is a PD-1 inhibitor, which is a protein that all of the body cells have in order to avoid being targeted by the immune system.
When a specific type of T-cell – called a tumor infiltrating lymphocyte (TIL) – goes to investigate suspicious activity, it looks to see if there is PD-1 on the surface of the cell. If there is, it leaves the cell alone since it’s then considered a normal body cell.
Cancer cells manipulate this process by creating a huge bubble of the PD-1 protein, so that when the immune cells see this, they assume it’s a normal group of cells. PD-1 inhibitors then act like a sponge to soak up the bubble of PD-1, leaving the tumor naked and exposed to the immune system. The result is that now the immune system has the ability to identify the tumor cells and attack them.
Given the high TMB, we knew that Korey had a very high chance of responding to PD-1 inhibitors and decided on a drug called Pembrolizumab. This drug is a 2nd generation PD-1 inhibitor but unlike the newer 3rd generation PD-1 inhibitors, it targets both the PD-1 ligand (the bubble) as well as the PD-1 receptors. We felt this would allow for better efficacy in Korey’s case.
Read About CTOAM's Success With Immunotherapy
Additionally, we created a diet plan for Korey that would enhance his response to immunotherapy. There is exciting new research showing that specific populations of bacteria can enhance immunotherapy by boosting the tumor infiltrating lymphocytes (TILS).
In one example, a recent study showed that Bifidobacterium increased tumor infiltration and IFN-γ production by CD8+ tumor-specific T cells and improved both basal tumor control and anti-PD-L1 efficacy via increased activation of splenic and intratumoral dendritic cells.
It is also well established that a diet high in fibre, and low in meat, greatly increases Bifidobacterium populations (Fessler et al., 2019).
Further, we provided recent clinical trial data from a recent cancer conference in March 2019, to show that the combination of this drug and a commonly available CTLA4 inhibitor (Ipilumumab), when given together, was very effective in treating late stage neuroendocrine cancers that were high grade such as Korey’s. Interestingly, this study showed that these drugs were not effective in low grade tumors (Patel et al., 2019).
We immediately provided Korey’s oncologist with a written report outlining our treatment recommendations.
However, given that high TMB is very rare in neuroendocrine cancers, and Korey’s oncologist was a top specialist in this type of cancer, our report was initially viewed with some skepticism. (Even top specialists are not able to keep up with all the new cancer research that comes out each day; they simply don’t have the time – which is why we, CTOAM, exist.) So Korey’s oncologist provided him with more palliative chemotherapy drugs (Cisplatin and Etoposide).
Korey and his oncologist were also concerned about reported side effects with these drugs. So, we presented them with peer reviewed research showing these drugs had minimal side effects in health individuals such as Korey (Som et al., 2019).
Given our experience with Pembrolizumab, we knew that these chemotherapy drugs could actually improve the chances of the immune drug working, since these chemotherapy drugs tend to increase the amount of PD-1 ligand that the tumors express.
While Korey’s oncologist remained reluctant, he did suggest that he’d be willing to do a test run of the drug if the current chemotherapy failed. At that point Korey’s insurance would also cover the cost of the drug; the FDA had already approved this drug for any cancer with MSI-high, MMR-Deficient of high TMB (as was Korey’s case).
To ensure Korey had a chance of receiving these drugs if his current oncologist not agree, we sent Korey for a second opinion with an oncologist who we had worked with and who was a specialist in immunotherapy and precision oncology. This specialist reviewed our reports and agreed that this was the best course of action and that he would prescribe these drugs if Korey’s current oncologist denied him.
After completing 6 courses of chemotherapy, Korey’s oncologist took him off the drugs since they were starting to produce side effects – and, while Korey had experienced an initial response, the drugs had now stopped working and his disease was advancing.
In September, 2019 Korey agreed to start Pembrolizumab, with the intent of adding Ipilumumab at a later date if there were no side effects and if the single agent drug was not effective.
We checked in with Korey on a regular basis over the next few months to ensure he was not experiencing side effects and had no obvious disease progression.
Korey was ecstatic. He said he had never felt this good and was living life to the fullest. Importantly, he did not experience any side effects whatsoever and reported that he was actually starting to his gain his normal weight back.
Early January, we shared exciting new data with Korey showing that a simple exercise supplement called creatine, was effective at increasing the efficacy of immune checkpoint inhibitors. The researchers concluded that creatine supplementation and PD-1 inhibitors worked synergistically, tipping the metabolic scales in T cells' favor and enabling them to avoid exhaustion and fight cancer effectively for an extended period (Di Biase et al., 2019).
Happily, Korey recently shared his latest bone scan which showed no evidence of metastatic disease in his bones and that a previous resected bone tumor was repairing itself! Importantly, Korey reported that his eyes were now white and that the yellowing, caused by damage to his liver from metastasis, was gone.
We are eagerly awaiting Korey’s next round of imaging. However, in the case that he stops responding, we have an additional immune drug to apply (Ipilumumab), as well as an arsenal of targeted therapies to try. So either way, there is much hope for Korey. And in the meantime, he’s been able to enjoy spending quality time with his family and get back to living his life.
This is the power of precision oncology!
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 research and patient advocacy 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.
Get a Precision Second Opinion now!
Di Biase et al., (2019). Creatine uptake regulates CD8 T cell antitumor immunity. The Journal of Experimental Medicine; jem.20182044 DOI: 10.1084/jem.20182044
Fessler et al., (2019). Exploring the emerging role of the microbiome in cancer immunotherapy. Journal for ImmunoTherapy of Cancer; 7 (108).
Patel et al., (2019). A phase II basket trial of dual anti–CTLA-4 and anti–PD-1 blockade in rare tumors (DART) S1609: The neuroendocrine cohort. 2019 AACR Annual Meeting. Abstract CT039. Presented March 31, 2019.
Som et al., (2019). Immune checkpoint inhibitor-induced colitis: A comprehensive review. World J Clin Cases; 7(4): 405-418.
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