Have you heard about an exciting new approach in cancer treatment that aims to give the right drug to the right patient at the right time? This concept goes by many names, such as personalized or precision medicine or even tailored therapy.
Personalized medicine uses information about a person to prevent, diagnose and treat disease. It helps doctors choose treatments based on a person’s genes or other features of the type of cancer the person has.
Just like each person in this world is unique and different, so are people’s cancers. No two are completely identical. Every cancer has a different genetic make-up. A portion of these genetic changes “drive” tumour growth. The idea of personalized medicine is to use therapies to target those specific genetic changes that cause each individual cancer to grow and progress.
With advances in the technology used to study cancer, it is now possible to learn the genetic make-up of each person’s cancer and then try to match a specific drug to the genetic changes found within it.
This concept is a big change from the usual way of designing a treatment strategy for patients, which is based on how cancer cells look under the microscope. In recent years, uncovering the genetic make-up of many types of cancers, such as breast, brain, colon, and esophagus cancers have found that they are more complex than previously thought.
Many of these cancers are not really a single disease, but rather contain subtypes, each with their own unique genetic make-up and clinical outcome. This information is changing the way cancer is diagnosed and is leading to more tailored treatments.
There is still a lot to learn, but doctors hope that personalized medicine will mean that people with cancer have fewer side effects and stay cancer-free for longer after treatment.
Personalized medicine success stories
Personalized medicine, although still in its infancy, is being used worldwide to treat cancer patients. One of the greatest personalized medicine success stories center around the treatment of a rare type of blood cancer called chronic myeloid leukemia (CML) and a drug called imatinib, more commonly known as Gleevec.
CML is cancer of the white blood cells caused by chromosome abnormalities. In most CML cases, a piece of chromosome 22 swaps places with part of chromosome 9. This is called a translocation and it appears to cause over 95% of CML cases. Scientists later figured out that 2 genes (named BCR and ABL1) are fused together as a result of the translocation – and this fusion can cause CML.
In the early 1990s, Gleevec was created to target the BCR-ABL translocation. When it was tested in CML patients in a phase I study for safety, almost every single patient’s cancer was improved. This rarely happens. Results from additional clinical trials were very successful, which led to Gleevec being approved as a CML treatment in Canada in 2001.
About 90% of CML patients treated with Gleevec are still alive after 5 years. A recent study found that a large percentage of these patients continue to be cancer-free more than a decade after their diagnosis.
This success story was one of the first instances when scientists understood what caused a particular type of cancer and made a specific drug to treat it.
Thanks to an improved understanding of the genetic make-up of other types of cancer, Gleevec is also being used for certain cancers of the stomach and digestive system as well.
Another success story of personalized medicine was the development of a drug called trastuzumab (Herceptin). In a proportion of all breast cancer cases, there are too many copies of a gene called HER2. These cancers (termed HER2+) are highly aggressive and often have a poor prognosis. Herceptin was developed to treat women with HER2+ breast cancer and it has made a big impact, such as improving survival for women with advanced HER2+ breast cancer from 20 months to 5 years.
There also can be too many copies of the HER2 gene in other cancers, including a proportion of stomach, esophageal, colon and lung cancers. People with these cancers could also potentially benefit from a therapy like Herceptin.
The challenges of personalized medicine
While personalized medicine is a rapidly evolving field, there are many challenges that need to be overcome before it can become a common reality for all cancer patients in the clinic. Five of the main challenges include:
(1) Identifying and understanding the “drivers” of cancer growth
Advances in technology are providing a wealth of information about the genetic make-up of cancers, allowing scientists to develop more tailored treatments. When the first human genome was sequenced, it cost more than $2 billion and took a decade to complete. Nowadays, tumour-sequencing which studies the genetic make-up of a patient’s tumour, can be determined for a few thousand dollars.
However, the results generated from these studies provide a vast amount of information and have uncovered a level of complexity relating to cancer that far exceeded many people’s expectations. How do scientists use this enormous volume of genetic information to choose the right drug for a patient?
To address this challenge, the key molecules within a cancer cell that are “driving” the cancer to grow need to be identified. By finding the molecules that are responsible for cancer progression, such as HER2, it may be possible to target them with specific drugs.
At this point, scientists only know a fraction of the drivers required for cancer growth. With thousands of genetic changes occurring within a single cancer cell, a tremendous amount of research is required to find out which molecules are the drivers and which are “passengers” that do not cause cancer growth.
Thus, further research is needed to bring these genetic discoveries to fruition in the clinic. Research in the lab will help us understand how each driver contributes to cancer and whether it should be targeted by cancer therapy.
(2) Identifying drugs that can target these drivers
Drugs are not available for every genetic change known to drive cancer growth. While this is an active area of research, it will take more time to develop additional cancer drugs.
Although there are drugs available for some of the drivers, the proportion of patients whose cancers contain that driving mutation can be low. In some cases, the number of patients for a particular cancer type who contain a specific driver can be less than 10%. Thus, only a small percentage of patients would benefit from these drugs. With time, new drugs should become available to target more drivers of cancer growth.
(3) Finding new ways to overcome drug resistance
There is room for improvement for personalized medicine. Drugs like vemurafenib (Zelboraf) to treat melanoma skin cancer containing a genetic change in the BRAF gene, or crizotinib (Xalkori) to treat lung cancer with a genetic change in the ALK gene have not been able to provide long-term benefits. In both cases, a patient may only respond partially to the therapy and it is often short-lived.
Drug resistance to therapies that have shown more sustained benefits, like Gleevec and Herceptin have also been observed. This happens because cancer is constantly evolving and often develops further genetic changes, or mutations, to adapt and grow back after treatment.
When one genetic pathway is targeted by therapy, cancer cells can evolve and turn on another so they can continue to grow and progress. This has been a major challenge in terms of personalized medicine.
How do we overcome it?
Similar to an approach used to combat AIDS, researchers have proposed using combination therapy. There is ongoing research trying to figure out which approach is best.
For example, do you combine the personalized therapy with another drug that targets the resistant pathways turned on within the cancer cells? Can you combine personalized medicine with immunotherapy, which harnesses a patient’s immune system to fight cancer? In this case, a personalized medicine approach would be used to shrink the tumour as much as possible, then immunotherapy could be given to recognize the remaining cancer cells that were resistant to the first treatment. With further research, we may know the best approach to improve the effectiveness of personalized medicine.
(4) Designing better clinical trials to test new treatments
Currently, new cancer treatments are initially tested on patients with advanced cancers in which all other treatment options have failed. These cancers have evolved tremendously over time as a result of previous treatments and are incredibly hard-to-treat.
There is growing acceptance in the research community that drugs for personalized medicine need to be tested earlier before the cancer has so greatly evolved. This means giving the right drug to the right patient at the right time.
This may require monitoring the genetic changes happening in cancers over time. With the development of liquid biopsies, researchers could examine tumour DNA within blood samples. This new technology would allow doctors to non-invasively monitor the genetic changes of cancer over time and help influence treatment decision-making. It could also help form the basis of new clinical trials.
(5) Testing the use of personalized medicine in the clinic
One of the main challenges of personalized medicine is whether it can be feasibly carried out in cancer centers and hospitals across Canada. This would require a major change in how patient samples are collected and analyzed to inform treatment decision-making.
Currently, when pieces of a tumour are removed from a patient, they are preserved in a way that is easy to store and that accurately maintains the tissue architecture. This is critical for diagnosing cancer by the way it looks under a microscope.
However, this would need to change if personalized medicine is implemented for all patients. The traditional way to preserve cancer tissue isn’t always suitable to examine its genetic make-up.
In addition, is it possible for every cancer centre and hospital in Canada to have access to the technology needed to test the genetic make-up of every patient?
Can the healthcare system handle the cost of the expensive technology and genetic tests needed for every patient to truly benefit from personalized medicine? Experts would need to be hired to analyse the results and recommend which genetic changes are clinically relevant and have drugs to target them.
Researchers, healthcare providers and policy-makers will need to work together to address these major challenges as personalized medicine continues to move forward.
New approaches to move personalized medicine forward
Traditionally, treatment strategies have been decided by where cancers arise in the body and how tumours look under the microscope. Current research is challenging this standard practice by highlighting that cancers developing in the same part of the body can vary greatly in their genetic make-up.
Clinical trials generally enroll patients who have cancer in the same part of the body and they receive the same treatment approach. However, new clinical trial designs are emerging. For example, therapies are now being given according to the genetic features of the tumour.
For example, the drug vemurafenib (Zelboraf) is effective for patients with melanoma skin cancer that contains a specific mutation in the gene BRAF. However, this drug has also been shown to work for hairy-cell leukemia and some forms of thyroid cancer also containing this mutation. In fact, nearly two-thirds of cancers with this mutation are tumours other than melanoma. This means that this drug could potentially be used for a wider variety of patients and many types of cancer.
One of the emerging types of clinical trials to address this issue is called a basket clinical trial. It groups patients by the genetic changes present within a patient’s cancer, rather than the part of the body it started in. This means that patients whose cancers contain a specific mutation are eligible for treatment against that mutation regardless of their tumour type.
An example of a basket clinical trial is one being carried out by Dr Philippe Bedard at the Princess Margaret Cancer Centre. This study, funded in part by the Canadian Cancer Society, is for patients with advanced pancreatic or colorectal cancer that share a common genetic change in their tumours. This study may improve patient outcome, but the information gleaned from it could also be used to develop better treatment strategies for these two types of cancer.
Another new approach for clinical trial design is the umbrella clinical trial. It groups patients of the same cancer type, but gives them different drugs, matched to the genetic changes of each patient’s tumour. Umbrella trials can also test different drugs targeting different mutations in a variety of cancer subtypes.
For example, the BC Cancer Agency is carrying out the Personalized Oncogenomics (POG) clinical trials which involves patients with incurable cancers who provide fresh tumour and blood samples to identify the specific genetic changes within their cancers.
There is great potential for clinical trials like these to not only bring hope to cancer patients enrolled in these studies, but also inform new treatment strategies and increase the knowledge of cancer researchers and doctors alike.
Will personalized medicine overtake conventional therapy for the treatment of cancer? Will they work best together or is one better than the other?
One specific trial, termed SAFIR02, is comparing standard treatment to personalized medicine for metastatic breast cancer. Chemotherapy is being compared to 8 different targeted therapies given to patients based on the genetic make-up of their tumour. This trial will help test whether personalized medicine can improve the outcome for women with breast cancer compared to the standard way of treating this disease.
Further studies will truly inform us whether personalized medicine is the breakthrough scientists hope it will be.
What’s next for personalized medicine?
Scientists around the world are developing tests to advance personalized medicine. Research is ongoing to provide further insight to the massive amount of genetic data accumulated in the clinic.
For example, mouse “avatars” are being used for drug testing for patients. Tumour pieces are taken from a patient and grown in multiple mice. Once the tumours grow, drugs are tested on the mice to predict which drug would work best in the patient. This has shown some initial success in the lab, and it has quickly become commercialized.
However, there are many practical issues preventing this approach from being used routinely in treatment decision-making.
First, it can take months for tumours to grow in mice, which is a long time for some patients who may have a short survival. The tumour may evolve differently in the mouse than in the patient over that time span. Second, only a few drugs could be tested at once using this approach. This approach is also extremely expensive. Last, these experiments are performed in mice that lack an immune system, which is a key component of tumour development.
Avatars are best used to provide insight into general treatment strategies, allowing researchers to study the initial responses to treatment as well as drug resistance.
A second type of approach for treatment decision-making is the use of circulating tumour cells from patients. These cells are taken from a patient’s blood, grown in a petri dish in the lab, then tested for their response to various drugs.
A third approach is growing cells in a 3D format rather than flat on a petri dish. The tumour cells are put into a semi-solid substance that contains nutrients needed for cell growth. The cells grow as “organoids” that recreate the architecture of the tissue they came from. This more realistically mimics how cancer grows in the body, which may make drug testing results more applicable to patients. The disadvantage of this technique is that it can take weeks to grow the cells this way in order to test drugs on them. More research is needed to see if this approach can be used for routine drug testing.
It is highly likely that these lab tests will not be used for all patients. More feasibly, they can help researchers learn more about how people might respond to personalized medicine. Before each of these lab tests become commonplace, researchers will need to confirm that they can be beneficial in terms of guiding treatment decision-making and that the results obtained provide long-lasting benefit to patients.
To successfully integrate personalized medicine into the clinic, the knowledge of the underlying science needs to be more closely integrated with treatment strategies. Luckily, in many hospitals, teams of doctors and scientists are working together to solve many of the challenges outlined in this article. This will help us close the gap of knowledge needed to best use personalized medicine for patient care.
Kelly Fathers, PhD