Stratified medicine: difficulties and opportunities in care

The attentive observer of health topics will have come across the term “personalized medicine” disproportionately frequently in recent times. But what exactly is behind it? A superficial fad or an opportunity for a healthcare system groaning under high costs?

>> It may sound strange that conventional medicine rarely offers “personalized” treatment. However, this is actually widely the case. In fact, alternative therapies derive a significant portion of their acceptance from this dilemma, as they place the patient at the center of diagnosis and intervention much more than conventional medicine. In conventional medicine, however, illnesses are treated first and sick patients secondarily. As is well known, we are talking about the treatment of high blood pressure, adult-onset diabetes, a breast tumor, etc. The individual patient initially plays a rather subordinate role. Guidelines, derived from evidence-based medicine, specify the options for action.
This is anything but a reproach to the responsible actors. Up to now there have been hardly any opportunities to involve the individual patient in a therapy decision in the way that is actually necessary. After all, no two people are alike. And if you look closely, there are hardly any identical clinical pictures, even if the name of a disease might suggest that.
Because of this dilemma, the drugs used to treat an illness are statistically evaluated in terms of their effectiveness and tolerability for a more or less large test population. The active ingredient is first tested in a wide variety of biochemical-pharmacological models in a test tube or on an isolated animal organ such as the heart, liver or a blood vessel, then in various animal models and finally on test subjects and patients. This step-by-step approach enables reliable statements to be made about the basic effectiveness and tolerability of the drug, and only if the benefit/risk assessment is clearly in favor of the benefit side will the drug be granted market access through approval by international or national authorities. However, these statements have to do with the Individuals have a certain degree of uncertainty because they occur in the form of a more or less extensive Gaussian distribution.
People have gotten used to it because there is no alternative. However, if you choose the test population large enough, you will sometimes observe radical “outliers”, which can be catastrophic for both those affected and possibly also for the drug. Deviations towards “ineffectiveness” are just as possible as deviations towards an individual overdose when used in principle correctly, which manifests itself in intolerance or even relevant toxicity for the patient.
Individual variations
But how is a doctor supposed to know whether a patient who is about to receive a drug that, according to a statistical assessment, helps most, but by no means all, those suffering from a particular disease will actually benefit from the drug and also tolerate that drug well?
The causes of such individual deviations from the norm are differences in the genetic makeup of people (Fig. 1 ). In order to be able to recognize and interpret these, the doctor has to look into the genomes - i.e. directly into the genetic information - of the patient. And that is possible today.
The new procedures are referred to as “molecular diagnostics”. They form the basis for personalized or stratified medicine with the aim of dividing a group of patients who all suffer from the same disease into at least three subgroups: a first group of patients who actually benefit from the drug, a second group of patients , whose members cannot benefit from the drug due to genetic constraints, and a third group who experience significant side effects when given the drug.
The consequences that will arise if this technical potential is exploited will amount to a paradigm shift. We will see change in the foreseeable future; away from treating a disease and towards treating a patient with a very specific genetic makeup. And this is a huge opportunity for patients, but also for the healthcare system. Treating patients with a drug that is approved for the disease the patient is suffering from, but which cannot work for that person due to physiological characteristics, is not only unethical, but is also a waste of resources.
sources that are urgently needed
where they are needed in the system.
Examples
Examples will be used to explain how important it would be to implement stratified medicine measures as quickly and as comprehensively as possible.
The first two examples come from the problem area of tumor therapy. The aim here is to diagnose genetic changes in the tumor in order to be able to use this additional information to treat the patient as specifically and thus as successfully as possible. The relevant mutations that need to be detected or excluded as biomarkers have been acquired by the tumor cells and form part of the pathomechanism of the disease. In most cases, the detection or exclusion of the mutation is mandatory because the active ingredients that are to be used for therapy were tested on stratified patient groups and approval was expressly only granted in combination with the test. (La Thangue/Kerr, 2011, 587; Peng Soh et al., 2011, 1621; Savonarola et al., 2012, 277)
The first example involves the two recombinant antibodies cetuximab (Erbitux®) and panitumumab (Vectibix®), which are approved for the treatment of colon or colon cancer. Both antibodies block a growth factor receptor - the epidermal growth factor receptor (EGFR) - on the surface of the tumor cells (Fig. 2).
By occupying the receptor, the antibodies prevent the tumor cells from being stimulated to continually divide by a growth factor. The prerequisite for the use of these two antibodies is of course that the tumor cells actually have this growth factor receptor, which must be checked diagnostically before the therapy decision is made (detection of target expression).
As plausible as this concept was and is, the therapeutic successes that could be achieved with these antibodies were relatively disappointing. The problem that tumors pose is that they are genetically heavily modified. And this all the more the more advanced the tumor is.
A frequently observed change, especially in colon carcinomas, is the receptor-independent activation of a downstream signaling pathway. For example, signal transmission gets out of control when a certain gene, the ras gene, mutates in such a way that the corresponding RAS “switch protein” can no longer carry out its switch function correctly because the molecular switch can no longer be switched off (see Fig. 2c). It is then no longer of any use to block the growth factor receptor with one of the two antibodies, as this blockage is functionally ignored by the permanent activation of a signal transduction component inside the cell.
This hypothesis was confirmed in clinical studies. As predicted, treatment with the antibodies proved to be much more effective in patients without a mutation in the ras gene compared to treatment in patients whose tumor cells carried a mutated ras gene (Karapetis et al., 2008, 1757). The regulatory authorities reacted quickly and restricted the use of the antibodies to patients suffering from colon carcinoma without a ras mutation. The diagnostic exclusion of a mutation in the ras gene is therefore a prerequisite for the use of the two antibodies cetuximab (Erbitux®) and panitumumab (Vectibix®) for the treatment of EGF receptor-positive colon carcinoma.
The second example concerns the relatively new active ingredient afatinib (Giotrif®). Afatinib is a tyrosine kinase inhibitor that inhibits signaling from all homo- and heterodimeric forms of the ErbB family. The active ingredient binds irreversibly to the receptors ErbB1, HER2 (ErbB2), ErbB3 and ErbB4 and is only indicated for first-line therapy in patients suffering from metastatic non-small cell lung cancer (NSCLC) whose tumor cells have a mutation in exon 19 (del19 ) or exon 21 (L858R) of the EGF receptor. These two mutations are so-called activating mutations, which, like the mutation in the ras gene described above, lead to a switch function being lost in the sense that the switch remains permanently switched on. Afatinib then binds to this defective switch and irreversibly inactivates it.
In order to illustrate how important these diagnostic differentiations are, four fictitious study scenarios are described for the two therapies in Table 1, which show the consequences if patient stratification using suitable biomarkers is omitted.
100 patients each are treated fictitiously, with 100% of tumor cells expressing the target structure for the active ingredient. For the antibodies in the first example this is the epidermal growth factor receptor (EGFR), for the small molecule afatinib these are receptors from the ErbB family. The average response to therapy under optimal conditions is assumed to be 80%. The four study groups differ in the activation of the primary and secondary targets. In the case of antibody therapy, the activation of a secondary target, the permanent activation of the ras protein, must be excluded in order to be able to expect a clinical response.
In the case of treatment with afatinib, however, the primary target (a member of the ErbB receptor family) must be activated by a mutation in order to expect a clinical response. As can be easily seen, the clinical response rates observed in the four study populations are dramatically different.
The following conclusions can be drawn from this simple example:
1. Target expression is not necessarily a predictor of clinical response.
2. A poor clinical response does not mean that the drug is “bad.”

In addition to these acquired biomarkers, which are only expressed in the pathologically changed cells and must be detected from them, there are also therapy-relevant biomarkers.
markers that are inherited and therefore present in all cells. These can therefore also be detected from all cells. These are mutations in genes that code for proteins that have no relevance to the disease, but with which an active ingredient can come into contact after the patient has taken it. These proteins include transporters that try to prevent the active ingredient from entering the system, transporters that specifically introduce active ingredients into specific cells, a variety of detoxification and inactivation enzymes, enzymes that serve to regenerate cosubstrate systems, etc. These proteins are common the active ingredients taken are chemically changed, for example to prepare them for excretion. Or they are chemically modified to activate an inactive active ingredient – a so-called prodrug – in the body.
Two examples:
Many small-molecule drugs are chemically modified in the liver by members of the cytochrome P450 enzyme family. This generally makes the molecules more water-soluble and can therefore be more easily excreted via the kidneys. If such a chemical modification is not possible for a particular active ingredient because the necessary enzyme is not synthesized at all or is synthesized in an inactive form due to a mutation in the corresponding gene, patients will sometimes experience massive side effects when taking the medication as prescribed because the active ingredient is in the Compared to the normal situation, it is eliminated far too slowly. Conversely, an amplification of the gene for the modifying enzyme can also occur. The active ingredient is then excreted so quickly that no therapeutic effect can be expected.
This has been empirically examined for a number of psychotropic drugs (Fig. 3). The relative drug doses shown in the figure are equivalent effective doses for poor metabolizers (PM), who do not have an active metabolizing enzyme, for intermediate metabolizers (IM), who only have half of a normal enzyme complement, for normal metabolizers (extensive metabolizer/EM), which have the normal enzyme content, and for super rapid metabolizers (ultra rapid metabolizer/UM), which have significantly too high an enzyme content due to gene amplification (Stingle et al., 2013, 273).
If these peculiarities are known, the problems can be easily corrected by simply adjusting the dosage (Fig. 4).
A second example is even more impressive. As we haven't known for so long, the old active ingredient tamoxifen, which has been very successful in the treatment of breast and ovarian cancer, is a prodrug, i.e. a molecule that is only chemically converted into its active form in the organism by various representatives of the group of cytochrome P450 enzymes Endoxifen is converted. Endoxifen blocks the estrogen receptor, which, like the above-mentioned growth factor receptor EGFR in colon carcinoma, mediates growth signals - but here in breast and ovarian cancer.
Tamoxifen is indicated for women who are undergoing “chemopreventive” treatment after surgery for a tumor whose cells contain an estrogen receptor. The idea is to block the growth of residual tumor cells that could not be surgically removed by depriving these cells of the ability to send growth stimuli into the cell nucleus via the estrogen receptor.
Affected women take the drug for years, and the strategy is very successful. However, not as successful as would theoretically be expected. The reason, as we now know, is that some patients are unable to convert the ineffective tamoxifen into the active form, endoxifen. Large, retrospective studies have shown that this is fatal for these women. Although their tumor contains the estrogen receptor, these women should have been treated at the time as patients whose tumors do not express the estrogen receptor because they cannot generate the active form of the blocking agent. Studies on biopsy material from patients who have already died demonstrate this shockingly clearly (Schroth et al., 2009, 1429; Regan et al., 2012, 441). (Fig. 5).
Today, so-called aromatase inhibitors offer a much more tolerable alternative treatment option. The active ingredients from the aromatase inhibitor group prevent the tumor cells from synthesizing estrogen. This means that no estrogen can bind to the estrogen receptors present in the cells. Therapy with aromatase inhibitors achieves a result that is completely analogous to that of tamoxifen therapy - a potentially life-saving option for the affected patients.
Based on this data, the American FDA (Food and Drug Administration) now recommends genetic testing of patients before a decision is made to use tamoxifen. In Europe people are much more reserved here.
Genetic diagnostics increases the efficiency of
health system
Many other examples could be listed where therapy could be significantly optimized today. Diagnostics - and especially genetic diagnostics - takes on a new quality here: it complements the classic field of disease-related diagnostics with diagnostics that provide information about whether and how drugs can work on a particular disease. This is in fact a completely new quality of diagnostics, which in the vast majority of cases is completely independent of the disease and the aim of which is to stratify patients into a group of responders, a group of non-responders and a group of adverse drug reactions. responders.
As a consequence, personalized/stratified medicine will not only make necessary therapies more effective and more tolerable for certain patients. It will also help to use the immense amounts of money that our health system now consumes more effectively. To speak of a “deceptive package” here, as can be read in recent critical articles, does not do justice to the good cause. It is more correct to speak of a “change in strategy”. A change in strategy, however, with extremely positive aspects - for the patient as well as for the healthcare system, which is groaning under immense costs. <<

>> It may sound strange that conventional medicine rarely offers “personalized” treatment. However, this is actually widely the case. In fact, alternative therapies derive a significant portion of their acceptance from this dilemma, as they place the patient at the center of diagnosis and intervention much more than conventional medicine. In conventional medicine, however, illnesses are treated first and sick patients secondarily. As is well known, we are talking about the treatment of high blood pressure, adult-onset diabetes, a breast tumor, etc. The individual patient initially plays a rather subordinate role. Guidelines, derived from evidence-based medicine, specify the options for action.
This is anything but a reproach to the responsible actors. Up to now there have been hardly any opportunities to involve the individual patient in a therapy decision in the way that is actually necessary. After all, no two people are alike. And if you look closely, there are hardly any identical clinical pictures, even if the name of a disease might suggest that.
Because of this dilemma, the drugs used to treat an illness are statistically evaluated in terms of their effectiveness and tolerability for a more or less large test population. The active ingredient is first tested in a wide variety of biochemical-pharmacological models in a test tube or on an isolated animal organ such as the heart, liver or a blood vessel, then in various animal models and finally on test subjects and patients. This step-by-step approach enables reliable statements to be made about the basic effectiveness and tolerability of the drug, and only if the benefit/risk assessment is clearly in favor of the benefit side will the drug be granted market access through approval by international or national authorities. However, these statements have to do with the Individuals have a certain degree of uncertainty because they occur in the form of a more or less extensive Gaussian distribution.
People have gotten used to it because there is no alternative. However, if you choose the test population large enough, you will sometimes observe radical “outliers”, which can be catastrophic for both those affected and possibly also for the drug. Deviations towards “ineffectiveness” are just as possible as deviations towards an individual overdose when used in principle correctly, which manifests itself in intolerance or even relevant toxicity for the patient.
Individual variations
But how is a doctor supposed to know whether a patient who is about to receive a drug that, according to a statistical assessment, helps most, but by no means all, those suffering from a particular disease will actually benefit from the drug and also tolerate that drug well?
The causes of such individual deviations from the norm are differences in the genetic makeup of people (Fig. 1 ). In order to be able to recognize and interpret these, the doctor has to look into the genomes - i.e. directly into the genetic information - of the patient. And that is possible today.
The new procedures are referred to as “molecular diagnostics”. They form the basis for personalized or stratified medicine with the aim of dividing a group of patients who all suffer from the same disease into at least three subgroups: a first group of patients who actually benefit from the drug, a second group of patients , whose members cannot benefit from the drug due to genetic constraints, and a third group who experience significant side effects when given the drug.
The consequences that will arise if this technical potential is exploited will amount to a paradigm shift. We will see change in the foreseeable future; away from treating a disease and towards treating a patient with a very specific genetic makeup. And this is a huge opportunity for patients, but also for the healthcare system. Treating patients with a drug that is approved for the disease the patient is suffering from, but which cannot work for that person due to physiological characteristics, is not only unethical, but is also a waste of resources.
sources that are urgently needed
where they are needed in the system.
Examples
Examples will be used to explain how important it would be to implement stratified medicine measures as quickly and as comprehensively as possible.
The first two examples come from the problem area of tumor therapy. The aim here is to diagnose genetic changes in the tumor in order to be able to use this additional information to treat the patient as specifically and thus as successfully as possible. The relevant mutations that need to be detected or excluded as biomarkers have been acquired by the tumor cells and form part of the pathomechanism of the disease. In most cases, the detection or exclusion of the mutation is mandatory because the active ingredients that are to be used for therapy were tested on stratified patient groups and approval was expressly only granted in combination with the test. (La Thangue/Kerr, 2011, 587; Peng Soh et al., 2011, 1621; Savonarola et al., 2012, 277)
The first example involves the two recombinant antibodies cetuximab (Erbitux®) and panitumumab (Vectibix®), which are approved for the treatment of colon or colon cancer. Both antibodies block a growth factor receptor - the epidermal growth factor receptor (EGFR) - on the surface of the tumor cells (Fig. 2).
By occupying the receptor, the antibodies prevent the tumor cells from being stimulated to continually divide by a growth factor. The prerequisite for the use of these two antibodies is of course that the tumor cells actually have this growth factor receptor, which must be checked diagnostically before the therapy decision is made (detection of target expression).
As plausible as this concept was and is, the therapeutic successes that could be achieved with these antibodies were relatively disappointing. The problem that tumors pose is that they are genetically heavily modified. And this all the more the more advanced the tumor is.
A frequently observed change, especially in colon carcinomas, is the receptor-independent activation of a downstream signaling pathway. For example, signal transmission gets out of control when a certain gene, the ras gene, mutates in such a way that the corresponding RAS “switch protein” can no longer carry out its switch function correctly because the molecular switch can no longer be switched off (see Fig. 2c). It is then no longer of any use to block the growth factor receptor with one of the two antibodies, as this blockage is functionally ignored by the permanent activation of a signal transduction component inside the cell.
This hypothesis was confirmed in clinical studies. As predicted, treatment with the antibodies proved to be much more effective in patients without a mutation in the ras gene compared to treatment in patients whose tumor cells carried a mutated ras gene (Karapetis et al., 2008, 1757). The regulatory authorities reacted quickly and restricted the use of the antibodies to patients suffering from colon carcinoma without a ras mutation. The diagnostic exclusion of a mutation in the ras gene is therefore a prerequisite for the use of the two antibodies cetuximab (Erbitux®) and panitumumab (Vectibix®) for the treatment of EGF receptor-positive colon carcinoma.
The second example concerns the relatively new active ingredient afatinib (Giotrif®). Afatinib is a tyrosine kinase inhibitor that inhibits signaling from all homo- and heterodimeric forms of the ErbB family. The active ingredient binds irreversibly to the receptors ErbB1, HER2 (ErbB2), ErbB3 and ErbB4 and is only indicated for first-line therapy in patients suffering from metastatic non-small cell lung cancer (NSCLC) whose tumor cells have a mutation in exon 19 (del19 ) or exon 21 (L858R) of the EGF receptor. These two mutations are so-called activating mutations, which, like the mutation in the ras gene described above, lead to a switch function being lost in the sense that the switch remains permanently switched on. Afatinib then binds to this defective switch and irreversibly inactivates it.
In order to illustrate how important these diagnostic differentiations are, four fictitious study scenarios are described for the two therapies in Table 1, which show the consequences if patient stratification using suitable biomarkers is omitted.
100 patients each are treated fictitiously, with 100% of tumor cells expressing the target structure for the active ingredient. For the antibodies in the first example this is the epidermal growth factor receptor (EGFR), for the small molecule afatinib these are receptors from the ErbB family. The average response to therapy under optimal conditions is assumed to be 80%. The four study groups differ in the activation of the primary and secondary targets. In the case of antibody therapy, the activation of a secondary target, the permanent activation of the ras protein, must be excluded in order to be able to expect a clinical response.
In the case of treatment with afatinib, however, the primary target (a member of the ErbB receptor family) must be activated by a mutation in order to expect a clinical response. As can be easily seen, the clinical response rates observed in the four study populations are dramatically different.
The following conclusions can be drawn from this simple example:
1. Target expression is not necessarily a predictor of clinical response.
2. A poor clinical response does not mean that the drug is “bad.”

In addition to these acquired biomarkers, which are only expressed in the pathologically changed cells and must be detected from them, there are also therapy-relevant biomarkers.
markers that are inherited and therefore present in all cells. These can therefore also be detected from all cells. These are mutations in genes that code for proteins that have no relevance to the disease, but with which an active ingredient can come into contact after the patient has taken it. These proteins include transporters that try to prevent the active ingredient from entering the system, transporters that specifically introduce active ingredients into specific cells, a variety of detoxification and inactivation enzymes, enzymes that serve to regenerate cosubstrate systems, etc. These proteins are common the active ingredients taken are chemically changed, for example to prepare them for excretion. Or they are chemically modified to activate an inactive active ingredient – a so-called prodrug – in the body.
Two examples:
Many small-molecule drugs are chemically modified in the liver by members of the cytochrome P450 enzyme family. This generally makes the molecules more water-soluble and can therefore be more easily excreted via the kidneys. If such a chemical modification is not possible for a particular active ingredient because the necessary enzyme is not synthesized at all or is synthesized in an inactive form due to a mutation in the corresponding gene, patients will sometimes experience massive side effects when taking the medication as prescribed because the active ingredient is in the Compared to the normal situation, it is eliminated far too slowly. Conversely, an amplification of the gene for the modifying enzyme can also occur. The active ingredient is then excreted so quickly that no therapeutic effect can be expected.
This has been empirically examined for a number of psychotropic drugs (Fig. 3). The relative drug doses shown in the figure are equivalent effective doses for poor metabolizers (PM), who do not have an active metabolizing enzyme, for intermediate metabolizers (IM), who only have half of a normal enzyme complement, for normal metabolizers (extensive metabolizer/EM), which have the normal enzyme content, and for super rapid metabolizers (ultra rapid metabolizer/UM), which have significantly too high an enzyme content due to gene amplification (Stingle et al., 2013, 273).
If these peculiarities are known, the problems can be easily corrected by simply adjusting the dosage (Fig. 4).
A second example is even more impressive. As we haven't known for so long, the old active ingredient tamoxifen, which has been very successful in the treatment of breast and ovarian cancer, is a prodrug, i.e. a molecule that is only chemically converted into its active form in the organism by various representatives of the group of cytochrome P450 enzymes Endoxifen is converted. Endoxifen blocks the estrogen receptor, which, like the above-mentioned growth factor receptor EGFR in colon carcinoma, mediates growth signals - but here in breast and ovarian cancer.
Tamoxifen is indicated for women who are undergoing “chemopreventive” treatment after surgery for a tumor whose cells contain an estrogen receptor. The idea is to block the growth of residual tumor cells that could not be surgically removed by depriving these cells of the ability to send growth stimuli into the cell nucleus via the estrogen receptor.
Affected women take the drug for years, and the strategy is very successful. However, not as successful as would theoretically be expected. The reason, as we now know, is that some patients are unable to convert the ineffective tamoxifen into the active form, endoxifen. Large, retrospective studies have shown that this is fatal for these women. Although their tumor contains the estrogen receptor, these women should have been treated at the time as patients whose tumors do not express the estrogen receptor because they cannot generate the active form of the blocking agent. Studies on biopsy material from patients who have already died demonstrate this shockingly clearly (Schroth et al., 2009, 1429; Regan et al., 2012, 441). (Fig. 5).
Today, so-called aromatase inhibitors offer a much more tolerable alternative treatment option. The active ingredients from the aromatase inhibitor group prevent the tumor cells from synthesizing estrogen. This means that no estrogen can bind to the estrogen receptors present in the cells. Therapy with aromatase inhibitors achieves a result that is completely analogous to that of tamoxifen therapy - a potentially life-saving option for the affected patients.
Based on this data, the American FDA (Food and Drug Administration) now recommends genetic testing of patients before a decision is made to use tamoxifen. In Europe people are much more reserved here.
Genetic diagnostics increases the efficiency of
health system
Many other examples could be listed where therapy could be significantly optimized today. Diagnostics - and especially genetic diagnostics - takes on a new quality here: it complements the classic field of disease-related diagnostics with diagnostics that provide information about whether and how drugs can work on a particular disease. This is in fact a completely new quality of diagnostics, which in the vast majority of cases is completely independent of the disease and the aim of which is to stratify patients into a group of responders, a group of non-responders and a group of adverse drug reactions. responders.
As a consequence, personalized/stratified medicine will not only make necessary therapies more effective and more tolerable for certain patients. It will also help to use the immense amounts of money that our health system now consumes more effectively. To speak of a “deceptive package” here, as can be read in recent critical articles, does not do justice to the good cause. It is more correct to speak of a “change in strategy”. A change in strategy, however, with extremely positive aspects - for the patient as well as for the healthcare system, which is groaning under immense costs. <<