Personalized and Targeted Therapies

Even though two people have the same type of cancer, for example both may have lung cancer, the growth rate, aggressiveness, and response to treatment may be totally different. This is down to the different genetic code of the cancers.  Indeed these two patients may need completely different treatments and if you use the same standard therapy it may work in one but not the other. 

By studying a tumour’s genetic makeup, oncologists are able to analyse the genetic changes that are responsible for the cancer growth and possibly match a right targeted therapy unique for that individual.  This strategy is also known as personalized or precision medicine. This is done through the mutation testing of a biopsy sample taken from the patient’s tumour. Targeted therapies are becoming more common as doctors and scientists are inventing ever more drugs that specifically  hone in on a particular protein/mutation.  Oncologists these days need to have a good understanding of molecular oncology and genetics to offer their patient the best possible treatment. 

Targeted Treatments

Personalized treatments are designed to target the specific genes and proteins found within a tumour that help the cancer to grow. While not all cancer types are able to have targeted treatments, if your oncologist does not look for these mutations then targeted therapy will not even be an option. 

There is a tremendous amount of scientific investigation being undertaken to develop new targeted therapy and the future is likely to see personalized treatment methods as the standardized norm of treating most if not every cancer. 

Types of Targeted Therapy

There are basically two typical types of targeted therapy.

• Monoclonal antibodies: These drugs work to stop a specific target around the outside of a cancer. They are delivered as an IV infusion in the hospital. 
  
  
• Small-molecule drugs: These small-molecule drugs are typically taken orally as pills and can be taken at home.
  
  

Solid versus Liquid Biopsy

• Solid Biopsy: This is a standard way to obtain genetic information. A sample of the cancer is removed from the body using a needle or via surgery. Sometimes a patient may have undergone previous surgery to remove the cancer for example a colectomy to remove a colon cancer. That cancer is normally stored in a pathology lab for years and the specimen can be used at a later date to perform genetic testing. The disadvantages of a solid biopsy is that it requires a procedure to remove the tissue. The advantage is that it is usually more accurate than liquid biopsy.
  
  
• Liquid Biopsy: Cancers can release their DNA into the bloodstream. Using sensitive laboratory methods, this DNA can be isolated and analysed. By taking a blood sample also known as a liquid biopsy, genetic tests can be performed. The advantage is that it is more convenient than taking a solid biopsy. The disadvantage is that it is 20-50% less accurate and if the tumour doesn’t release DNA into the bloodstream the test will be negative.
  
  

Single versus Multi-Gene Testing

• Single Gene: This process is when a single or several limited number of genes are tested. The genes being tested are known to be frequently mutated in a particular type of cancer for example EGFR, ALK and ROS-1 in lung cancer or k-ras, n-ras and b-raf in colorectal cancer. The disadvantage is that if a mutation is present on another gene such focussed testing will miss it. The advantage is that it is cheaper than multi-gene testing and yields results faster.

• Multi- Gene: This process is when many genes which could harbour mutation are tested in one sitting, sometimes a few hundred genes. The advantage is that it cast the net wide to look for potential targets across the board. The disadvantage is that it is more costly than limited gene testing and may take 2-4 weeks turnaround time.
  
  

Basic List of Gene Mutations and their Associated Targeted Therapies 

Breast	ER/PR positive	Aromatase Inhibitor eg. letrozole, exemestane, anastrozole Tamoxifen  CDK4/6 inhibitors – palbociclib, ribociclib, abemaciclib
Breast	HER2 amplification	HER2 inhibitors eg. trastuzumab, pertuzumab, TDM-1, lapatinib
Lung	EGFR mutation	osimertinib, afatinib, dacomitinib, gefitinib, erlotinib
Lung	ALK rearrangement	alectinib, ceritinib, crizotinib, lorlatinib
Colorectal	kras/nras wild type	EGFR monoclonal antibodies eg. panitumumab, cetuximab
Stomach	HER2 amplification	HER2 inhibitors eg. trastuzumab
Ovarian  Breast Pancreatic Prostate	BRCA mutation	PARP inhibitors eg. olaparib
Brain	MGMT methylation 1p19q loss of heterozygosity	Alkylating agent chemotherapy eg. temozolomide, PCV chemotherapy
Multiple Cancers	MSI (microsatellite instability)	Immunotherapy example pembrolizumab and nivolumab
Multiple Cancers	PD-L1 protein expression	Immunotherapy example pembrolizumab, nivolumab, atezolizumab

Remember:

– If the tumour does not have a target, the targeted therapy usually will not work.

– The degree and duration response to a drug varies from person to person

– After a period of time the cancer can develop resistance to the treatment by developing further mutations. At this time, repeating the genetic profiling of the tumour may be necessary 

– Targeted therapy can also cause side effects.