More about salivary gland cancers

SCGUK’s first ever meeting for those living with Acinic Cell Carcinoma took place online on the 15^th of July. There were nearly 20 people taking part, including those living with AcCC, their family members, and researchers into this rare salivary gland cancer.

There was a chance for everyone to introduce themselves, and share something of their story, including diagnosis and treatment pathway. Then Dr Rob Metcalf*, a medical oncologist who is also a researcher in the field of salivary gland cancers, talked to us about some of the latest findings in the world of Acinic Cell Carcinoma research. A summary of his talk is provided below.

All salivary gland cancers have different, specific biology

There are around 24 different types of salivary gland cancer. They are all different diseases, and you’ve got to consider them as differently as if you were thinking about breast cancer and bowel cancer, from a medical oncology perspective. (In surgery and radiotherapy, treatment paths would be more similar. A surgeon might say – if it’s localised you remove the tumour. A radiation oncologist might say  – there are certain high-risk features, and you give radiotherapy after surgery for some patients and not others, but specific radiotherapies work for multiple salivary gland cancer types.) However, when it comes to drug treatments, every single salivary gland cancer is entirely different. Each cancer has a different biology, and so will have different optimal drug treatments. That’s why it’s important for us to understand the individual biology and workings of each different salivary gland cancer type.

Challenges in salivary gland cancer research

Generally, research studies in this area tend to be run with groups of patients with different types of salivary gland cancer, rather than there being studies about specific cancers. So, if you look at a study, there may be 20 patients, and of those 20 patients, maybe two will have Acinic Cell Carcinoma. It’s difficult to draw useful conclusions from such a small sample of people. The rarity of these cancers is partly responsible for this happening, as not only is it more difficult to get funding for research, it’s also harder to find the numbers of patients needed to get meaningful data from a trial. One of the reasons we set up Salivary Gland Cancer UK was to build networks between researchers and patients. This means patients can contribute to vital research into their own specific type of cancer by donating blood and tumour samples to lab work. They can also learn about, and be involved in, trials for new drug therapies and treatments.

What is driving Acinic Cell Carcinoma?

A research group from Germany have published the results of their research into what drives AcCC**. They have sequenced the genomes of a handful of patients with Acinic Cell Carcinoma and they’ve found a specific, recurrent genetic change. They found a relatively large number of genetic changes in each person, but they found one change, named NR4A3, in all of the patients in the study.

It’s a really important finding, because it gives researchers a focus to try and work out how to switch off the overactive cancer cell behaviour in AcCC. If this is the key genetic change driving Acinic Cell Carcinoma, how do you switch off this alteration, or how do you work out what this change is regulating, what it’s doing within the cell – and block it? At this stage, this is still an if. In the patients whose genomes were sequenced in this study, there were a wide range of genetic changes, so we can’t say for certain that the NR4A3 change is what’s driving the growth of each tumour. But because it’s occurring with such regularity it’s a very promising place to start.

Why understanding the biology of AcCC cells is so important

It’s very important that we understand Acinic Cell Carcinoma from a medical oncology perspective, in order to develop new drugs. It’s the start of the journey in the process of developing treatments, because you have to understand the biology of a cancer before you can develop a targeted drug trial.

Otherwise, the drug trial is just set up on the basis that there’s a new drug available – so let’s try it on this cancer and see if it works. It’s a very hit and miss approach.  There are a number of these types of drug trials for salivary gland cancers. When you get the results, some people may respond, and others won’t – and it’s very hard to pick apart why, or what is really working. This is particularly true when you are not only working with a small sample of people but also, the sample includes people with several different types of salivary gland cancer.

Q: Is the biology you’ve described for Acinic Cell Carcinoma uniform across everyone, or are there variations?

This genetic change was recurrent across all the Acinic Cell patients in this paper – around 15 people. But this isn’t a very large sample – and it is rare to see uniformity in biology. If you looked at a larger number of people, you would probably find that it’s not as simple as everyone with Acinic Cell having the same genetic change. If you look at other cancer types, there tends to be more than one genetic cause. In another form of salivary gland cancer, Adenoid Cystic Carcinoma, there’s one particular gene that you see occurring in around 60% of patients. Another 30% have a different form of this gene. The remaining 10% or so don’t express this gene – MYB – at all and we don’t yet know what causes their cancer.

We will probably find the same sort of variation in Acinic Cell Carcinoma. On top of that – the genetics of each individual patient’s cancer are different – so even if they have the same genetic mutation (NR4A3) the context in which it is found is still really important. If you’ve got one mutation and nothing else, you’ve got less interference in the over activity of that gene. If you’ve got one mutation and another 100 mutations, just tackling that one mutation alone might not work. It’s a question of identifying which, if any, of the genetic changes you have identified are important.

A potential new drug treatment for certain types of Acinic Cell Carcinoma

This is data that was presented at ASCO’s (American Society of Clinical Oncology) annual meeting in June 2020. It’s the world’s leading oncology meeting, focusing on drug therapies rather than surgical oncology or radiation oncology. It’s a study of a particular targeted therapy in salivary gland cancers. It exemplifies how we still group together salivary gland cancers. The study includes patients with Mucoepidermoid Carcinoma, Myoepithelial Carcinoma, and several other salivary gland cancers, as well as Acinic Cell Carcinoma. But we have to analyse them separately, because these are all biologically very different entities.

This study was asking: Is it possible to classify and treat patients by a specific genetic change, rather than by a specific salivary gland cancer? In this study, all the patients had the same change in a gene called HRAS, although they had several different types of salivary gland cancer. The patients were all given a targeted drug, Tipifarnib, and the size of their tumours was measured. A 30% or more decrease in tumour size is considered significant. There was some decrease in size in a third of the patients.

In this study, there was a single patient with Acinic Cell Carcinoma, whose tumour did decrease in size. Acinic Cell Carcinoma is a rare disease, and the HRAS mutation is a sub-group of the AcCC patient population. When you are a clinician working with patients with salivary gland cancers, this can be the level of evidence you are working with. Moving forward from here, we would ideally do two things in parallel. Firstly, a larger trial of 20, 30 people with Acinic Cell Carcinoma who have an HRAS mutation, to see if their tumour would shrink when taking Tipifarnib. Secondly, work in the lab, to understand more about the biology of Acinic Cell Carcinoma, to understand if – and why – this treatment might work, so the two pieces of research could feedback into each other.

Q How common is HRAS in Acinic Cell Carcinoma?

We don’t know for certain and more research needs to be done, but a ballpark initial figure might be 5%.

*Dr Metcalf divides his time between The Christie Hospital in Manchester, where he treats patients with all types of salivary gland cancer, and Manchester University, where he researches into salivary gland cancers, with a particular focus on Adenoid Cystic Carcinoma.

Links

**A link to the article about the NR4A3 Transcription factor research.

https://www.nature.com/articles/s41467-018-08069-x#author-information