Origin unknown – how pathology is helping to fight mysterious cancers

Pathology testing is crucial for the diagnosis of cancer, as well as providing guidance for the best treatment options.

Cancer treatment is highly specialised and many drug treatments are now given based on pathology results that show the drug is likely to be effective. However, this type of testing is limited to specific genes or panels of genes and is ordered when doctors already know some information about the cancer, specifically where in the body it is.

Determining the type or origin of a cancer may seem obvious; if cancer is found in the liver, it’s liver cancer right? Unfortunately, that is not always true.

If a person has cancer that spreads to another area of the body (metastasises), the secondary tumour usually has similarities to the original tumour. These similarities in the cells can be seen by a pathologist examining tissue from the tumour under a microscope.

So, when a cancerous tumour is found that does not have characteristics common to cancers from that part of the body, it is usually thought to be a metastasis – a cancer that has spread from another cancer elsewhere in the body. When the original site of the cancer cannot be identified this is called Cancer of the Unknown Primary (CUP).

Professor Sean Grimmond is from the Victorian Comprehensive Cancer Centre (VCCC) where research is focused on cancers of unmet need; these are cancers where the survival rate is poor or treatment options are limited. Cancer of the unknown primary falls in this group.

According to Cancer Council Australia, CUP is the fifth most common cause of cancer death in men, and fourth in women.

This means CUP causes more deaths than melanoma or leukaemia.

One reason CUP has a high mortality rate is that it is so difficult to target treatment.

Prof Grimmond says, “In these cases, choosing a drug just based on the tissue of origin can be like guesswork.”

Fortunately, advances in genomic sequencing and scientists’ understanding of cancer DNA are helping to shape new methods for testing and treatment of CUP.

At the VCCC researchers are using genomic sequencing techniques to help patients with difficult to treat cancers.

Prof Grimmond explains: “We want to move from using the microscope for this type of diagnostic to using DNA, because the pattern you see in the DNA can be used to infer the organ of origin.

Also the damage to the DNA in the tumour reflects what type of event triggered the mutation in the DNA that led to cancer developing; whether it’s UV light or smoking or old age. So if you’re looking at a patient that has a cancer of the unknown primary in their pancreas, but you can see a pattern that reflects UV damage, you would start to think that skin could be the origin.”

This research could lead to the development of new specialised pathology tests for CUP patients to help quickly determine the original cause of their cancers, enabling targeted treatment faster.

“This could improve the time to treatment drastically and offer hope for patients where current treatment options are very limited,” says Prof Grimmond.