Nuances of a catchy phrase

Personalized medicine: you have to admit these words have a very good ring to them. It is probably what everyone thinks they are getting whenever dealing with a doctor, although the reality often falls short of that. While obviously every doctor will treat each patient with an individual approach based on their past history, it is not easy or cheap to dish out diagnostic testing to collect personal medical data to manage treatment. Therefore the amount of such testing will be governed by the amount of money available to pay for such tests for everybody.

However, personalized medicine has a more defined niche. It refers to the use of DNA sequencing in order to formulate medical management. And even that is too broad of a statement, as the personalized medicine term has really entrenched itself in cancer management.

Why has this coveted phrase been so effectively hijacked by the cancer arm of medical world? That is because no other field of medicine has probably experienced a greater renaissance thanks to the introduction of next-generation DNA sequencing (our latest, greatest methods that allow entire human genome sequencing at very affordable costs). Per share of sequencing data produced, cancer sequencing dwarfs any other projects. In fact, the knowledge and understanding of cancer has grown so rapidly in the previous decade, and what it means for its treatment, that it is typically referred to as a new paradigm.

Perhaps this is a bit unfair to all of the other aspects of medicine that already utilize DNA sequencing for diagnosis and patient treatment. Genome sequencing can be used for diagnosing literally thousands of different conditions! So to make a bit of a distinction between cancer precision medicine and the rest of the medical world, another catch phrase used to describe it is“precision oncology”.

This phase also has a good ring to it and appropriately captures the essence of how much the field of cancer has transformed!

Cancer research and a treatment renaissance

Let me give you an idea of what we are talking about. The vast majority of all human genomes assessed in the world have been that of sequenced cancer biopsies. Thousands upon thousands of biopsies have been investigated for their DNA mutations, and along the way this information has been catalogued into a comprehensive database of all of the mutations involved in cancer development of all kinds. This project was cutely named The Cancer Genome Atlas with its abbreviation TGCA representing the four nucleotides found in our DNA. It is expected that eventually we will truly know all of the molecular aberrations that occur in all types of cancer. If that was not enough, we are now pushing the boundary in attempting to understand what the precancerous mutation drivers are, as these are the mutations that start setting cells up towards cancer development. The Pre-Cancer Genome Atlas if you will. The goal would be to start monitoring for these mutations and then to intervene prior to cancer ever having a chance of taking a foothold in your body.

Adapted from Muir P et al. 2016. Genome Biol 17(1): 53

In turn, this understanding of the molecular pathology of cancer cells has ushered in a wave of new cancer drugs on an unprecedented scale. Approximately one third of all of our modern approved drugs are for cancer treatment. This includes both the cytotoxic drugs and targeted therapies. Cytotoxic drugs are the chemotherapy drugs, compounds that target the fast-dividing cells and therefore do not discriminate between healthy cells and cancer cells. Targeted therapy drugs are those that specifically target cancer cells, and they take advantage of some molecular feature that is associated with cancer cells only. When you think of personalized medicine, you might as well think of targeted therapies in that same thought.

What is personalized, what is not?

It is not as simple as it seems, however, for targeted therapy is a blanket term but distinctions can also be made. Targeted therapies can be personalized or non-personalized, and it is the personalized targeted therapies that are used based on the molecular features discovered in each person's cancer. Non-personalized targeted therapies do not probe for such information, and are used on the assumption that the cancer feature that will be targeted by the specific drug will be present. Indeed, some types of cancer are always present with some specific aberration.

Personalized medicine is often described as the future of medicine, but I can agree and disagree with that statement. I disagree because it is already here and available for those who can afford it and gain access to it; but agree because one day it will be the standard, replacing the current approaches of chemotherapy and radiation. In fact, some targeted therapies have already entered as the standard approach towards cancer cures, but it is a trickle when compared to what is available out there.

For all of that touting, why is personalized medicine trickling in as a standard approach so slowly?

Well, first of all, it has to combat and replace the burden of tradition. Standard approaches in cancer treatment have been around for many decades now, and very few oncologists have been trained in personalized medicine based on cancer DNA sequencing. It will take some time to replace them or train them, and it is not a trivial task.

Tied to this tradition of old ways is an abundant dose of scepticism towards these novel methods. There still seems to be a tremendous amount of debate about the validity of personalized medicine, and whether this new approach to cancer treatment can truly produce better results than the tested standard methods, as if none of these targeted therapies were FDA approved and had not gone through extensive clinical trials.

So let's look at some data, shall we?

Meta-analysis evidence

As mentioned, dozens and dozens of personalized targeted therapies have been approved, and the literature on this topic is extensive, as we are literally talking about hundreds of clinical trials around the world. It would take years to wade through this amount of information! Luckily, some researchers have, providing us with some amazing literature on the comparison of outcomes between personalized and non-personalized medications in clinical trials.

The same group of authors published 3 separate papers comparing the results of phase I clinical trials, phase II clinical trials, and the type of cancer involved, along with FDA-approved drugs and their performance. Every drug is required to go through three clinical trials before it can be approved for market distribution. These summary papers were published in 2015 and 2016, and assessed information from up to 2013. Obviously much more has happened since then, and in the world of precision oncology, research tends to be moving faster, but that is the best data package we have today.

Let's start with Phase I clinical studies of targeted therapies, as these are the first human trials when investigating a potential drug for future public use. The paper compared outcomes based on 346 clinical trials that involved 13,2013 patients. Of these, only 2,655 patients were actually enrolled in trials that assessed personalized targeted therapy. This means that the patients’ cancer biopsy was analyzed for either DNA information or for the presence of some protein specific to cancer.

Here comes the good stuff: personalized targeted therapy showed a better response rate (the percentage of patients responding to treatment, either partially or completely), with a median of 31.1% across the studies. Non-personalized targeted therapies produced only a 5.1% response rate which was very similar to what was observed with standard chemotherapies, which were at a 4.7% rate.

What was interesting is that authors also looked at the personalized treatments from two perspectives: those that used cancer DNA information to select the therapy, and those that used the analysis of the proteins found in the cancer. Cancer treatments selected based on DNA had a higher median response rate than those using protein information, at 42% versus 22.4%, respectively. The drugs that showed the best response, those that the authors referred to as "super performer" drugs with an over 60% response rate among patients, were found in 8 out of 9 cases to be personalized targeted therapy drugs.

Another way to measure the success rate of cancer clinical studies is with what is referred to as a progression-free survival, or the length of time that patients do not see their cancer worsen. With personalized therapies, the patients’ median survival rate without cancer progression was 3.3 months versus 2.5 months for standard therapies. These are median values, meaning some patients did not respond well, while some responded very well.

But here is some particularly revealing information that perhaps could explain part of the confusion regarding the efficacy of the use of targeted therapies in cancer treatment: if targeted therapies were used without looking at cancer for personalized information such as DNA mutations or what protein levels are present, then they were not more effective than cytotoxic agents! The median patient response rate for targeted therapies that were developed without a biomarker was only 5.1%.

So unless you are using targeted therapies based upon the molecular profiling of a cancer biopsy, such drugs don't seem to be any better than chemotherapy. In fact, they could perhaps be even worse, as we shall see right away.

When it came to the summary of phase II clinical studies of targeted therapies, the authors reviewed 570 studies comprising 32,149 patients! Although once again, 8,078 of these patients were actually enrolled in the personalized treatment trials. But also once again, the outcomes were pretty impressive!

Personalized targeted therapies demonstrated a median response rate of 30% compared to the 11.9% rate observed with standard chemotherapies. But non-personalized targeted therapies had the worst rate with only 4%! If this subtle distinction between personalized and non-personalized therapies is not properly understood, it could inadvertently paint a bad picture for the personalized therapies, and might explain certain hesitations by oncologists to try these new regimens.

These trends persisted for the other two metrics measured. The median progression-free survival rate for the personalized approach was 6.9 months, for chemotherapy it was 3.3 months, and for non-personalized targeted therapies it was 2.6 months. Finally, the median overall survival rate in the same order was 15.9 months, 9.4 months, and 8.7 months, respectively. Once again, personalized treatments based on a genomic marker had a higher median response rate, and prolonged the median progression-free survival rate as well as the overall survival of patients than personalized treatments using a protein marker.

In the final publication by the authors, they compared the effect of already FDA approved drugs for cancer treatment. It included 58 drugs based on 112 clinical trials that included 38,104 patients. You probably won't be shocked to learn that personalized therapy was associated with a higher patient response rate of 48%, a longer median progression-free survival rate of 8.3 months, and a longer median overall survival of 19.3 months. Contrast this with 23%, 5.5 months, and 13.5 months respectively, for the latest and fanciest non-personalized chemotherapy options.

The authors concluded that "a personalized strategy was an independent predictor of better outcomes and fewer toxic deaths." That sounds pretty amazing, and brings great hope towards improving our chances with combating cancer. That provides tons of accumulated evidence, as we are talking about the summarizing of over 1000 clinical trials with nearly 75 000 participants! That also occurred in a relatively narrow time window. Needless to say, genome sequencing has become even more ubiquitous since then, and it will be exciting to see what the future updates will reveal on the clinical trials commenced since.

But there is still more to this story. These studies, as amazing as they are, summarize tons of small trials where specific cancer patients were being selected. Now the big question remains, can we take cancer patients as a whole, sequence their cancer DNA, and treat them accordingly. In other words, does this approach translate to the general population? There are now studies coming out in support of that as well, and that deserves its own post. Ultimately, it will be such randomized precision medicine clinical trials, where patients are assigned to any type of personalized targeted therapy based on their molecular profiling, that will be the ultimate proof to demonstrate why all or nearly all cancer patients should be sequenced in order to properly treat their disease.

If such a service is required for you right now, certainly Merogenomics can be of assistance. And if you know anyone affected by cancer, let them know. They should know their options too.

This article has been produced by Merogenomics Inc. and edited by Kerri Bryant. Reproduction and reuse of any portion of this content requires Merogenomics Inc. permission and source acknowledgment. It is your responsibility to obtain additional permissions from the third party owners that might be cited by Merogenomics Inc. Merogenomics Inc. disclaims any responsibility for any use you make of content owned by third parties without their permission.

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