The Value of Comprehensive Somatic Tumour Mutation Genetic Profiling

 In Cancer

A tool that is used increasingly in looking out for effective treatment options in the management of advanced cancers after standard lines of treatment have been exhausted is a test called tumour mutation/genetic profiling. These tests are done locally or overseas.

Frequently it does not entail a new biopsy of existing tumours in the body but retrieving tumour specimens obtained from previous biopsies or surgeries done to remove the primary tumours.

There is occasionally a need to obtain fresh tumour specimen by a new biopsy if the old biopsy/surgical specimen cannot be processed for technical reasons or if there is a need to ascertain if the present tumours harbour different mutations from the original tumour sample.

Liquid biopsy may also be done via a simple blood sampling without the more invasive core tumour biopsy procedure but the sensitivity of liquid biopsies in detecting these circulating tumour DNA in the blood stream may be limited if the cancer burden is low or the natural biology of the tumour is such that it does not shed its DNA into the blood stream.

We will illustrate a case example to full explain how comprehensive tumour mutation genetic profiling may help open up more therapeutic options in the management of advanced cancers.

Case Example Summary

  • Middle aged lady diagnosed with stage III NPC. Received appropriate standard treatment but one year later found to have widespread metastatic disease in lungs, liver, bones, mediastinal nodes on PET scan.
  • Doctor recommended sending the previous tumour specimen obtained from the biopsy done 1 year ago for comprehensive genetic profiling.
  • (While based on a real life case, the details have been changed to maintain anonymity)

Below are frequently asked questions:

What is this profiling test?

It is a test to detect mutations within the tumour sample that are known to be the main engines in driving cancer growth and spread.

There are as many as a hundred of these known mutations that are important. Most tests nowadays try to detect hundreds of them during each profiling.

What can we do with the results?

A minority of mutations detected in such profiling tests are important as there are very effective drugs available to target the specific mutation found with high response rates.

However several mutations detected may not have any available effective drug targeting it. Nevertheless, it may be still useful to know if a target is in sight as the effective drug may be just one step away from being approved for routine use in the clinical setting.

The pace of drug development has certainly quickened within the last decade.

What are the chances of a positive result in terms of a driver mutation with an available drug targeting it being found?

While low (less than 5%) in most instances but when detected, it may present a lifeline in prolonging survival for the patient with advanced cancer who have exhausted all known lines of therapy. In some rare tumours, the chances are higher (20-30%) in detecting such a mutation.

What about the other mutations detected? There are several mutations in the tumour genetic profiling report that are termed Variants of Unknown Significance (VUS). What are they?

These are mutations found in the tumour that are not usually seen in the normal population. The impact of these mutations on tumour behaviour or the tumour response to specific drugs have not been investigated or reported in medical research.

These findings are still useful in case future reports of their impact or an available drug is developed targeting that specific mutation.

Also these mutations may be the subject of ongoing clinical trials studying drugs targeting these mutations, tumour harbouring these mutations may render the patient eligible for enrolment in these clinical trials.

(Lucence Tissue500Tm)

  • FGFR3 S249C is a hotspot mutation in exon 7 of the FGFR3 gene
  • C.746C>G; p.S249C
  • Gain of function with homodimer stabilisation resulting in constitutive ligand independent cell proliferation and increased AKT signalling
  • Most frequently found in urothelial cancers

Returning to our case example, fortunately for this person, a mutation not known to be frequently found in nasopharyngeal cancer (NPC) is detected – a fibroblastic growth factor receptor (FGFR) mutation.

This mutation is found more commonly in bladder cancers. Indeed a drug was recently approved for use targeting this mutation.

In this patient’s case 8 other mutations of unknown significance (VUS) were also reported and the attending doctor can keep a look out for future drug approvals addressing these mutations or see if there is a suitable clinical trial to enrol in.

The FGFR Landscape

The FGFR Landscape

The FGFR Landscape

FGFR mutations are rare. Only 7% in one study of all solid tumours.

Chart comparision of the FGFR Landscape

Chart comparision of the FGFR Landscape

But when we focus on certain groups of tumours like bladder cancer and breast cancer, the incidence increases to 20-30% of these tumours. So long as the driver mutation is present, it can be targeted regardless of type of tumour. In our case example it is NPC.

FGFR3 S249C Knockdown Effects

FGFR3 S249C Knockdown Effects

FGFR3 S249C Knockdown Effects

Drug development is not that simple. A lot of hard work has been completed to prepare the ground prior to its development through clinical trials.

The laboratory bench work will have to first determine what is the effect of this mutation. The early work done usually more than 10 years prior to drug being used in the clinical setting is key.

In this specific mutation in FGFR3, researchers found that it is possible to knockdown the function of this mutation and the result is a marked reduction in the ability of the cancer cell harbouring this mutation to grow and spread. Restoration of this mutation function induced a rebound in the cancer cell growth and spread capability.

Erdafitinib: A Pan-FGFR Inhibitor

Pan-FGFR Inhibitor

Pan-FGFR Inhibitor

We also know through laboratory studies that not all cancer cells with this FGFR3 mutation will respond well to a drug targeting this specific mutation. Cancer cells that concurrently harbour other different mutations may be resistant to this drug as the other mutations are stronger in their growth driver signals.

This explains why when the drug (Erdafitinib) developed to shut down the FGFR mutation cancer driving properties were tested in humans with tumours harbouring the FGFR mutations, only less than 10% achieved a complete response and less than 50% had a confirmed response (partial and complete added together).

Metabolic Complete Response After 3 Months of Erdafitinib

Fortunately for our case, the FGFR3 mutation was the only driver mutation found without competing driver mutations that will confer resistance. Complete response was achieved with erdafitinib within 3 months. More studies will have to be done investigating combination drugs shutting down all relevant mutations to achieve a complete response as such consistently.

It does not mean that this person is cured of NPC. If the drug is stopped, the cancer will most certainly become active again. Or in future, the other as yet dormant clones harbouring other driver mutations may rear their ugly heads and result in new sites of cancer progression.

We will explore further options to control such challenging cancer treatment resistance in future articles.

Recent Posts

Leave a Comment

A Singapore Success Story: The Fight Against Liver Cancer