Individualized Medicine Vs. Precision Medicine by DR

COMMENTARY: Individualized medicine vs. precision medicine BY DR. JOE OLECHNO, SENIOR RESEARCH FELLOW, LABCYTE INC. HERE ARE PEOPLE who will die of cancer this week vivo testing to mitigate some of the deficiencies inherent with genomics even though there are drugs that could help them. approach alone. At the same time, hundreds of patients will undergo cancer chemotherapy that, while Problem 1—Mutations in DNA are debilitating and expensive, will not cure them not clear signs of the cause of the cancer (or disease) of their disease. Typically, genomic analysis is used to determine what mutation While cancer is a formidable foe, there is causes the cancer. Sometimes the therapy works and at other times, a way to improve patient care and prognosis the patient goes through debilitating chemotherapy only to find immediately. that there was no impact on the cancer. In fact, the cancer may Researchers in Finland, Sweden and Spain have modifiedex-vivo test- have grown and further mutated during the time of the treatment, ing of cancer cells with significant results. Their approach is far more gaining both mass and genetic changes so that it is even harder to “personalized” than traditional precision medicine. Their results are treat with supplementary rounds of chemotherapy. Tstriking. They provide a missing link between genomics-based mutation While it may seem obvious that if you sequence the tumor and find determination and clinical efficacy. the genetic flaw that causes the cancer, addressing that flaw specifically Precision medicine (also referred to as “personalized medicine” or should result in remission. In fact, this desired outcome is sometimes PM) appears to many patients, doctors and researchers to be a golden achieved. Yet despite the apparent causal relationship between muta- highway from disease identification to cure. The idea of interrogating tion and cancer, clinicians often do not see a good correlation between the genome of a particular cancer to determine its Achilles heel is intui- the identification of the genomic mutation and successful treatment. tively satisfying and understandable. There are, however, significant Researchers at the Wellcome Trust Sanger Institute and their col- problems.1,2,3 First, PM is neither personalized nor precise. PM strives leagues have observed that healthy skin tissue—tissue that appeared to identify the appropriate biomarker (usually a DNA mutation but normal by any measure—was full of somatic DNA mutations. DNA proteins, peptides and metabolites can stand as biomarkers as well) mutations in the apparently healthy skin were found at the same to categorize the patient as a member of a specificgroup of patients. level as the mutations in tumor cells.5 Not only did a quarter of The patient is treated with a drug that has shown positive results on all the healthy skin cells carry a cancer-causing mutation, but the previous members of the group. In other words, personalized medicine researchers found that these mutations were under strong posi- is actually population-based medicine. tive selection—that is, the number of cells carrying the mutations In contrast, the method described by researchers at the Institute of tended to increase even though there was no evidence of cancer. Molecular Medicine, Finland, determines empirically the best treat- This means that when an oncologist finds a cancer-causing muta- ment with what they call “individualized” medicine to differentiate it tion, it may not be the cause of the cancer jeopardizing the health from PM. They follow the determination of the appropriate therapy of the patient. It may just be along for the ride. But giving a drug with detailed genomics-based analyses of the patient and the cancer targeted to the harmless mutation delays getting the drug that will to develop an understanding of the mode of action of the therapy. By actually stop the cancer. All the while, the initial cancer drug may integrating the cure with an understanding of the genetic mutation, cause damage to healthy cells. they have changed the existing paradigm and created “individualized Similarly, researchers at Johns Hopkins showed that DNA analysis of system medicine.” The power of the individualized system medicine tumor cells tended to produce many false positives.6 They suggest that approach includes the ability to more quickly look at mechanisms of comparing the mutations in apparently healthy tissue with that of the action, assess drug combinations, understand drug resistance, position tumor will determine the true, cancer-causing genes. Unfortunately, and de-risk drug candidates and provide more rapid drug repositioning the data from the Wellcome Trust Sanger Institute mentioned above in a way that has not been previously achievable.4 suggests that healthy tissue contains many different mutations, and it is There are three critical problems with genomics-based PM. Two of unlikely that there is a single healthy genotype to use for comparison. these problems are intrinsic to the biology. Genomics-based science has Simply put, evidence of the existence of a mutation is not evidence of a identified exciting new methods of treatment and I do not call for its cause for cancer. Treating a patient based on a latent mutation may harm abandonment, but rather adding to the process the critical step of ex- the patient and delay helpful treatment.

Reprinted with permission from DDNews n May 2016, Volume 12, Issue 5 Old River Publications, LLC n 19035 Old Detroit Road n Rocky River, OH 44116 www.DDN-News.com n Tel: (440) 331-6600 n Fax: (440) 331-7563 Problem 2—Inability to reconcile Problem 3—Personalized medicine falls genomic data and phenotypic results back to guessing if no drug has previously been Two extremely good labs, the Cancer Genome Project and the Cancer found effective against a cancer associated Cell Line Encyclopedia, analyzed the DNA of hundreds of different with a new genomic mutation cell-lines. They also tested the cell lines against many different drugs Assuming that you correctly determine the mutation causing the can- to see how they responded. The data from both labs was analyzed by cer among all the other somatic mutations in the sample, you may find Quackenbush and colleagues7 who found that their genomic results a mutation for which no chemotherapy has been determined. The were spot-on. Both labs obtained very similar results when they ana- pharmacogenomic process can point you only to treatments that have lyzed the DNA from the same cell lines. However, when these labs already been verified. That means that the drug of choice has been tested identical drugs against these cell lines, they obtained dramati- tested in double-blind experiments and has gone through the required cally different results. If one lab found that a particular drug was effec- government licensing procedures for that particular cancer. While the tive against a target in a cell line, the same analysis in the other lab, number of therapies continues to grow, the personalized medicine pathway would miss (and would never even look to try) that some cancers can be cured by drugs not associated with a particular cancer. In essence, you would need to test all drugs against all cancers, a herculean feat with most existing proto- cols. Personalized medicine would not have pointed a doctor to using thalidomide9 or methotrexate10 against particular cancers, but individualized more frequently than not, gave contradictory results. systems medicine can help uncover new uses for existing drugs in an This means that even if finding DNA mutations meant that you orderly way. For example, researchers at the Institute for Molecular could choose a particular target or enzyme to block in the treatment Medicine, Finland (FIMM) have shown that the antiangiogenic renal of a cancer, you might not be able to choose the right drug. Each lab cancer drug axitinib11 can be repurposed against T315I-mutant BCR– could end up choosing a different treatment due to the difficulty in ABL1-driven leukemia. determining the correlation between drug and response. Guessing is still just guessing even if there is genomic data. Having phe- It is important that the two labs obtained almost identical results notypic results that show which drug or drug combinations kill a patient’s in their DNA analyses. This shows that they both use consistent sci- particular cancer is a significant advance. entific methods that others can replicate. One assumes that if they can match results analyzing DNA, they should also be able to get A Reasonable, Cost-Effective equivalent results in drug response experiments. The fact that they Complement to Genomics-Driven Testing do not suggests that the problem is not something as simple as com- Finding a mutation does not necessarily mean finding the cause of petence in scientific technique. the cancer. And even if the cause of the cancer is identified correctly, A recent publication in Nature Biotechnology8 highlighting that cer- it is not easy to determine which drug will be effective against that tain individuals are resilient to Mendelian childhood diseases despite mutation. What is the alternative? clear genomic evidence of the presence of the specific mutation is Researchers at FIMM12,13,14,15,16,17 and elsewhere have turned the just another example of DNA sequence alone not providing sufficient question on its head. Instead of trying to identify a mutation in the proof of disease. This paper amplifies the impact of problems 1 and 2. DNA and then trying to find a drug that addresses that mutation, By adding critical information, the ex-vivo individualized systems medi- they isolate cancerous cells from the patient. They then test those cine approach eliminates this problem and reproducibly generates the best cancerous cells against hundreds of possible drugs to see which drugs therapy for a patient’s particular cells. are effective against the cancer. In some cases, they use cocktails of

Reprinted with permission from DDNews n May 2016, Volume 12, Issue 5 Old River Publications, LLC n 19035 Old Detroit Road n Rocky River, OH 44116 www.DDN-News.com n Tel: (440) 331-6600 n Fax: (440) 331-7563 drugs to see if the combinations are more efficacious than single Testing drugs for efficacy before starting chemotherapy will reduce drugs. They frequently test the drugs at many different concentrations costly but futile rounds of therapy. It would also identify active drugs to better understand the potential dosing aspects. and let the patient and doctor make secondary decisions on price. Just because a drug works against isolated cancer cells ex vivo does This could increase competition and drive down prices, especially on not necessarily mean that it will work inside the body. However, the those drugs that show little if any efficacy. inverse of that statement, that if it does not work on cells ex vivo it is While PM may give lip service to non-genomic assays, by far unlikely to work in the patient, is most likely true. This is what the the greatest effort and the largest number of dollars are being researchers found. By screening the drugs against the patient’s cancer directed towards using genomic markers to determine healthcare. cells, they found other cancer drugs that were able to drive the cancer In part, this is because the success of the Human Genome Project. to remission while saving patients from ineffective treatments. Most Excellent scientists from the NIH, NCI, academia and private significantly, this was true even in patients who had already failed multiple industry combined to provide the first full human DNA sequence. rounds of chemotherapy. The question then was, “What’s next?” With hundreds of sequencers Chemotherapy has both monetary and health costs whether or not purchased and thousands of molecular biologists now trained, it leads to a cure. First-line treatments can fail and force the patient to how could all these resources be put to good (and desired by the alternatives. Every new round of treatment eats away at the window public) use? Healthcare was the obvious choice. But to the hammer, of opportunity to cure the disease. everything is a nail. The researchers at FIMM have developed an empirical, individu- I believe that there is a role for genomic analyses in healthcare, alized test that can screen hundreds to thousands of drugs against I just do not think that it will be the panacea that many suggest. I a patient’s particular cancer quickly and at low cost. The test can am especially concerned that excellent tools, like those developed eliminate chemotherapy that is highly likely to fail and it informs the by FIMM, are not being used by researchers locked into solely the clinician of the best options. With DNA analyses, as they describe in genomic pathway. their papers, individualized systems medicine can help expand the I urge clinicians and researchers to explore the work begun in understanding of cancers and guide future drug discovery. Finland. The procedures are straightforward and the results can While labs in Finland, Sweden18 ,19,20 and Spain21 are already inves- be rapidly available. The technique offers the promise of increased tigating the technique, more labs should be moving this forward. As remissions, reduced failure of chemotherapy and decreased healthcare a member of a family that has been struck multiple times by cancer, I expense. A multilevel winning strategy uniting ex-vivo testing with hate to think that I would need to book a flight to Finland in order to genomics-based analyses appears within our grasps, and we need to get the best options for chemotherapy. take hold. n

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