Julio’s Story

The Case of Julio – Squamous Cell Parotid Gland

View more case examples here

Download our brochures here (PDF)

Julio’s Story

In Dec 2016, Julio went in for surgery for what his doctors had diagnosed as a Warthin’s tumour (papillary cystadenoma lymphomatosum), which is a benign cystic tumour of the salivary glands.

However, during surgery, his doctors noticed a cancerous mass with finger-like projections protruding into the surrounding tissues. A new sample was taken and submitted for pathology.

Unfortunately, the tumour sample contained many immune and other inflammatory cells that hindered diagnosis. So while a first diagnosis of peripheral T-cell lymphoma was initially considered, in March 2017 his pathologists settled on a new one: poorly differentiated parotid squamous cell carcinoma (a major salivary gland).

His doctors suggested that extensive surgery followed by radiation therapy would be his only option, which would leave him significantly disfigured.

Julio wasn’t ready to just accept this, so he reached out to CTOAM.

How We Helped Julio

1. Introduced Advanced Diagnostics

We first reviewed Julio’s medical records and pathology reports. From these, we concluded that Julio’s case was unique and required a full genetic and molecular analysis.

For starters, his pathology showed a very high CD4/CD8 T-cell ratio of 25/1, whereas 2.0 is the normal ratio.

To explain briefly: T-cells are the arm of the immune system that attacks tumours. There are two main types of T-cells, with the helper and regulatory (TREGs) T-cells expressing CD4 and the tumour infiltrating (TILs) expressing CD8.

The CD4 positive cells (helpers/TREGs) are the first to arrive at the sight of a growing tumour. They relay important messages back to the immune system and tumour infiltrating cells (TILs), as well as release growth factors and resources needed to expand the TIL immune response.

The importance of this finding is that infiltration of regulatory T-cells (TREGs) into tumour correlates with poor patient prognosis because these cells release growth factors and resources that the tumour cells can hijack for their own purposes.

In other words, Julio’s tumours had initially started an immune response, but then his tumours hijacked the CD4 helper/TREGs to steal their growth factors and resources, and also halted the impending TIL immune response.

The CD4/CD8 ratio was important to us because it indicated that Julio’s tumours where immune-reactive, and therefore might benefit from immune-based treatments (more on this later).

We immediately obtained a sample of Julio’s tumour tissue and sent it for tumour DNA sequencing. We looked for cancer-causing mutations in the DNA of over 340 genes involved in head and neck cancers.

READ MORE ABOUT TUMOUR DNA SEQUENCING HERE

Secondly, we asked Julio to contact an independent community oncologist whom we’d worked with before, and who was willing to work with Julio and his treatment team via distance.

2. Conducted Patient Specific Research

Since Julio’s public system doctors had concluded the best course of treatment would be surgery followed by radiation, we viewed his medical records and the latest peer reviewed data to determine if this approach were going to be beneficial or not.

This is a very important step because radiation therapy is only beneficial in certain subtypes of head and neck squamous cell carcinomas. In fact, significant data exists to show that, although human papillomavirus (HPV)-positive head and neck squamous cell carcinoma is sensitive to radiation therapy, HPV-negative tumours are comparatively resistant to the treatment.

We also know that this phenomenon is largely due to the fact that HPV-positive head and neck squamous cell carcinomas do not express the programmed death one ligand (PD-1L), which reduces the effectiveness of radiation therapy in non-HPV positive cases.

In order to confirm whether Julio’s tumours expressed PD-1L (i.e. were resistant to radiation), we conducted a body-wide PD-1L expression test using a blood based liquid biopsy PD-1L ctRNA test.

Typically, we do this test on all of our patients to determine if the cancer is sensitive to PD-1 immune checkpoint inhibitors, such as pembrolizumab and nivolumab. However, in this case, the test was two-fold: not only would it allow us to determine if the radiation therapy prescribed by his doctors would benefit him (in the case of no PD-1L), it would also let us know if PD-1 inhibitors could play a role in his treatment (in the case of high PD-1L expression – see below).

A word on PD-1R/L checkpoint inhibitors

The PD-1 ligand is a protein that every cell in the body is required to have on its outside surface. It acts like a security guard, telling 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 some cancers, the tumours 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 tumours use to avoid detection by the immune system. The other two are known as the CTLA4 and the IDO axis.

Treatment with PD-1 inhibitors results in removal of the protective PD-1L blanket surrounding the tumours, resulting in reactivation of the immune system against the tumours. These drugs act like a vaccination and are given via injection every three weeks. Importantly, they have minimal side effects compared with standard radiation/chemotherapy.

We started using PD-1 inhibitors about four to five years ago, and they’ve had dramatic effects on some patients.

READ ABOUT OUR FIRST PD-1 INHIBITOR PATIENT HERE

A word on ctRNA-based testing of PD-1L

While the FDA has approved a variety of biopsy based PD-1L tests, these tests are, for the most part, fairly insignificant. This is because during the course of disease, different tumours interact with the immune system via the PD-1R/L signalling pathway at different times.

In other words, a specific tumour only needs to over-express PD-1L for a brief period of time in order to trick the immune system into leaving it alone.

In Julio’s case, the significance of the liquid biopsy version of PD-1 is two-fold:

  • Just because a single biopsy of a tumour does not show PD-1L expression, it doesn’t mean that other tumours in the body aren’t currently expressing it. If other tumours were expressing it, then he would be subject to radiation unnecessarily (recall sensitivity to radiation therapy is specific to head and neck tumours that have no PD-1 expression).

 

  • If the specific tumour tested does not show PD-1L expression (other untested tumours in the body may), then Julio may be refused immunotherapy treatment, which could be very beneficial.

 

READ MORE ABOUT LIQUID BIOPSIES HERE

3. Interim Treatment Support

Within 10 days, Julio’s liquid biopsy report came back and we were shocked to see that, unlike most non-HPV associated cases, his cancer was indeed negative for PD-1L expression. This meant that he’d more than likely receive a significant benefit from radiation therapy.

Happily, we were able to say with confidence to Julio, as well as his family and treatment team, that he was one of the rare HPV-negative cases that would respond to radiation therapy!

Unfortunately, these findings also indicated that PD-1 inhibitors would be unlikely to be effective for Julio.

4. Genetic Testing During Treatment

Within a month, we received the results from Julio’s tumour DNA testing…and we were shocked!

It turns out that Julio had 57 mutations – over twice as many than we’ve ever seen in a patient.

While there were a variety of potentially targetable mutations for Julio, we will only focus on the findings that have the most immediate significance to this case.

High Number of Mutations

The high amount of genetic mutations and the type of mutations we found showed us that Julio’s cancer is mismatched repair deficient (MMR). This is a unique situation where the genes involved in repairing DNA damage (including BRCA2) are mutated and broken.

This has three important implications for Julio:

(a) He should respond to exceptionally well to PD-1R/L immune checkpoint inhibitors, such as pembrolizumab and nivolumab, because the high number of mutations makes his tumours immuno-reactive.

(b) He will respond exceptionally well to radiation therapy as his tumour cells lack the resources to repair the DNA damaged by the radiation.

(c) The FDA recently approved pembrolizumab for any cancer that is MMR-deficient, so Julio more than likely could have his treatment covered by the Canadian medical system.

 

Implications of Julio’s BRCA2 mutations on his treatments

Furthermore, Julio had two BRCA2 mutations. One of his mutations was well known, but the other mutation was unique to him. In both cases, a stop codon had been inserted in the gene, resulting in a truncated version of the gene.

Mutations in BRCA2 have unique implications to causation and treatment: since BRCA2 is involved in DNA repair, then these mutations will help provide an exceptional response to both radiation therapy and pembrolizumab.

Furthermore, these mutations can lead to treatment with PARP inhibitors, which have recently been approved for cancers with germline (inherited) BRCA mutations.

A word on PARP inhibitors

PARP inhibitors work by targeting a signalling mechanism involved in DNA repair. Since Julio’s faulty BRCA2 genes are also involved in DNA repair, using a PARP inhibitor would result in his tumour cells being unable to repair DNA damaged by standard radiation (RT) and chemotherapy.

That is to say, the addition of a PARP inhibitor would provide significant benefits to standard chemotherapy and radiation. This approach is referred to as synthetic lethality.

Implications to Julio’s Family Members

However, the occurrence of these two mutations indicates there’s a significant chance that one of them is inherited. This means his other family members could also have the mutation, resulting an increased sensitivity to certain DNA damaging agents, including sun exposure and DNA damaging carcinogens.

In fact, given that these mutations occur at different points in the gene, it is highly unlikely that they occur in the same copy of the gene. Rather, they almost certainly occur on the two separate alleles (copies) of the genes. (Humans have two copies of each gene.)

With this in mind, we urged Julio’s family to seek further testing of his BRCA mutations to establish if one of them is found in both the tumour sample and the normal genes, or inheritable.

Typically, this test is covered by medicare in Canada and performed by a genetic counsellor. It’s a simple blood test to see if the mutation is also found in the normal cells. If it is, then further testing of second-degree relatives is required.

Julio’s treatment team offered to provide germline (inherited) testing of his BRCA2 mutation.

5. Outcome

Recently, we followed up with Julio and were not surprised to hear that he had a successful response to his radiation therapy and that his tumour had significantly reduced in size.

He is currently about to start immunotherapy with pembrolizumab.

However, we were not happy to hear that Julio’s genetic counsellors neglected to perform proper genetic testing of his BRCA2 mutation, as well as likely neglected to review the Foundation One tumour DNA testing results that CTOAM submitted.

The genetic counsellors claimed the mutation they looked at was not inherited. But they neglected to look at both of the mutations.

Clearly, this information could have significant consequences to Julio’s family!

We will follow up with Julio’s genetic counsellors to ensure they finish the job properly and test for the second BRCA2 mutation.

Since these drugs might be free for Julio, there’s a possibility that he can get the treatment he needs with far less stress and financial strain – and, significantly, without enduring the harsh side effects and limited benefits that chemotherapy would have provided him with.

Furthermore, when these drugs stop working, he will have a variety of other targeted therapies that will have the potential of providing him with more time, and still without the damaging side effects of standard chemotherapy.

6. Conclusions

As you can see, CTOAM’s advanced diagnostics, records review, personalized research, and consultations can result in significant benefits to a patient’s treatment 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 dealing with 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 you are doing all you can, and that you have access to the best treatments that medical science has to offer for your unique form of cancer. Contact us today at +1 (778) 999-5463 or email contact@ctoam.com.

 

Precision Oncology: The Future of Cancer Treatment, Now.