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Several genetic risk tests have been launched recently for common diseases such as breast cancer, prostate cancer, atrial fibrillation and myocardial infarction. Most agree that the genetic markers used are well-validated in the sense that the genotyping can be performed accurately and the markers used have been widely replicated as significant risk factors in several populations including tens of thousands of patients and controls. The relative risks conferred by the genetic risk profiles in these diseases equals or exceeds that of most conventional risk factors and are independent of them, including paradoxically, immediate family history. However, some have questioned the wisdom of introducing such tests when there are more sequence variants to be discovered or they would like to see more evidence confirming clinical utility vs. potential harms. Indeed, variants discovered in the future using genome-wide sequencing methods once costs come down will complement the common variants already reported and we agree that information from ongoing and future clinical utility studies will further establish how genetic risk tests complement conventional risk factors. Nevertheless, these tests further refine our assessment of risk and represent tools for more cost-effective prioritization of scarce resources for early detection and prevention of some of the most costly and deadly common diseases. Furthermore, we believe, it is the physician who is best positioned to interpret and act on these new genetic risk tests for common diseases.

In the 1980s and 1990s, there was an avalanche of disease gene discoveries for many of the rare Mendelian diseases such as cystic fibrosis, Duchenne’s muscular dystrophy and Fragile X mental retardation. However, these were diseases generally caused by high-penetrance variants in a single gene. The disease genes contain determinative variants with very high penetrance – for example, patients who have the trinucleotide repeat mutation within the Huntington’s disease gene, will all develop the characteristic movement disorder, chorea, as well as dementia, no matter what they do earlier in life. Conversely, patients who do not possess mutations in the Huntington’s disease gene will never develop Huntington’s disease, no matter what their environment is.

Common variants contributing to common diseases

  1. Top of page
  2. Common variants contributing to common diseases
  3. Multi-marker genetic risk profiles for prostate cancer define risk that is greater than that of family history
  4. Genetic risk profiles for the common forms of breast cancer
  5. Common genetic risk markers for myocardial infarction that are independent of conventional risk factors
  6. Should we wait until we discover all the genetic risk markers before using the validated markers discovered so far?
  7. Should we wait for decade-long randomized clinical trials before using genetic risk profiles for common diseases?
  8. What are the potential harms of screening with genetic risk tests?
  9. Will genetic risk profiles add to conventional risk to improve the cost-effectiveness of our healthcare system?
  10. Should individuals be able to access their genetic information directly?
  11. Disclosures
  12. Address
  13. References

Now, we have a new avalanche of genetic discoveries, this time in the common diseases. Common diseases generally do not follow a determinative genetic inheritance pattern like the Mendelian diseases; if anything, they may skip one or more generations or have no obvious family history. On the basis of large twin and family studies, we know that there is a significant genetic component to the risk of all common diseases; in fact, our genealogical analyses of extended families of many common diseases show that this component extends far beyond the nuclear family including up to 2nd cousins and much of it is not accounted for by family history of the disease in first degree relatives [1–6]. This paradox can be explained by the confluence of multiple genetic factors and the environment.

Over the last few years, we and others have carried out numerous hypothesis-independent genome-wide association and linkage studies using up to a million genetic markers including single nucleotide polymorphisms (SNP), leaving almost no common variation of the genome unturned. In many of the most common diseases, several genetic markers that confer significant risk have been found and widely replicated by a large number of major research groups. Just our group alone, using the Icelandic population as the discovery population and replicating the findings in collaboration with over 300 investigators around the world, has reported over 150 confirmed SNPs covering 30 common diseases and traits. These discoveries have expanded our knowledge of the pathogenesis of common diseases.

Currently, there are several common diseases where the discovered sequence variants account for a substantial proportion of overall risk and that are independent of conventional risk factors including immediate family history. While more sequence variants are expected to be discovered, we have already reached the point where genetic markers may be used to define some higher risk individuals before they become patients and display symptoms and signs of disease. These genetic markers reflect the patient’s intrinsic risk and are based on measuring the most stable molecule in the human body, DNA, and unlike many protein and RNA-based tests, do not show biological variation day-to-day or according to fasting or fed states. Furthermore, germline DNA markers do not need to be re-measured throughout the patient’s life – a given set of variants can be measured once at any time in an individual’s life using a blood sample or simple inner cheek swab. Therefore, genetic profiles may be useful additions to conventional risk assessments in certain clinical situations.

Multi-marker genetic risk profiles for prostate cancer define risk that is greater than that of family history

  1. Top of page
  2. Common variants contributing to common diseases
  3. Multi-marker genetic risk profiles for prostate cancer define risk that is greater than that of family history
  4. Genetic risk profiles for the common forms of breast cancer
  5. Common genetic risk markers for myocardial infarction that are independent of conventional risk factors
  6. Should we wait until we discover all the genetic risk markers before using the validated markers discovered so far?
  7. Should we wait for decade-long randomized clinical trials before using genetic risk profiles for common diseases?
  8. What are the potential harms of screening with genetic risk tests?
  9. Will genetic risk profiles add to conventional risk to improve the cost-effectiveness of our healthcare system?
  10. Should individuals be able to access their genetic information directly?
  11. Disclosures
  12. Address
  13. References

Without a doubt, the best way to deal with cancer is to detect it early. Prostate cancer would be considered a preventable disease if we found a way to detect and treat intermediate and high-grade tumours before they spread beyond the prostatic capsule. There is no chemotherapeutic agent that works for prostate cancer – once it spreads, a high percentage of patients die unnecessarily and the high prevalence of bone metastasis leads to a miserable and very costly quality of life during the long years before death. However, if caught and treated early, prostate cancer is curable. Every cancer found early vs. at a later stage saves the healthcare system hundreds of thousands of dollars.

Widespread screening using the imperfect biomarker, prostate specific antigen (PSA) has contributed to a 35% drop in the population age-adjusted mortality rate per 100 000 (according to the NIH supported SEER database http://seer.cancer.gov/statistics). This translated to a drop in annual prostate cancer deaths in the US from 40 000 in 1990 to 27 000 last year. The role of PSA and digital rectal examination screening in this dramatic drop in cancer death was supported by the PSA screening randomized clinical trial in Europe which showed a 20–27% drop in mortality in the screening vs. no-screening groups [7] (the NCI-run PLCO study so far has not demonstrated a difference in mortality; however, this trial has fewer observed endpoints and because of poor compliance, only 85% of the screening group had any PSA screening while 50% of the ‘standard of care control group’ was also screened as intensively by PSA, severely reducing the power of the study [8]. Many diagnosed prostate cancer patients will die of other causes than the cancer because prostate cancer does not progress to death as fast as many other cancers and most patients are older than 60. This has led to a call from some for active surveillance for evidence of progression in patients with the intermediate grade cancer before recommending definitive treatment [9]. However, a randomized clinical trial of patients diagnosed with intermediate grade prostate cancer in Scandinavia showed that the mortality rate in the watchful waiting group was twice that of the surgical treatment group when cancer was diagnosed before 65 years of age [10].

Despite screening for prostate cancer in the US, it remains the second deadliest cancer for men. In contrast to many other common diseases, there are not many factors available to risk stratify men for prostate cancer. The only conventional risk factors are family history of early-onset prostate cancer in first degree relatives and ethnicity (especially African-Americans). Therefore, fewer than 5% of white males are considered higher risk (about twofold) because of family history and by default, 95% are labelled as average risk. Higher risk men are recommended to have earlier screening [American Cancer Society (ACS), American Urological Association (AUA)] and to be biopsied at borderline levels of PSA [National Comprehensive Cancer Network (NCCN)].

Using large-scale genome-wide linkage and case-control association studies on prostate cancer, we and others have discovered 25 common germline variants that contribute to the risk of prostate cancer [11–21]. Each of these markers has been replicated by us and others in 8–15 populations totalling 20 000 patients and 50 000 controls. The risk compared to the general population at each marker has been estimated using these large datasets and it ranges from 1·14 to 2·65 in those who are homozygous. The risks may be combined by simple multiplication. This is justified because no interaction has been found between the markers and no model fits the data better than the multiplicative one (log-additive) [16,17,20] (Fig. 1). The nine significant markers found by the initial genome-wide association studies (GWAS) studies have a greater effect than the 16 new markers that have been found later through large-scale meta-analyses [20]. The genetic profile defines risk spanning 0·2 to over fourfold compared to the general population risk (Fig. 1). Two of these markers also define patients who have modestly increased likelihood of aggressive vs. less aggressive cancer at diagnosis [11,15].

image

Figure 1.  Prostate cancer risk across the general population based on a genetic risk profile. The 25 validated SNP markers together define relative risks from 0.2 fold to over fourfold compared to the general population. The x-axis shows the percentile in the general male population and the y-axis shows the relative risk at each percentile.

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Based on the current 25 replicated SNP markers, the upper 15th percentile of the population averages 2·1 fold risk for prostate cancer, top 5 percentile 2·8 fold, and the top one percentile 3·9 fold risk [20]. Given that white individuals have a 17% lifetime risk (SEER database), this translates into 34, 47 and 66% lifetime risk respectively. However, this test is not determinative. High-risk patients are not destined to develop prostate cancer and low-risk patients are not immune from it. Rather, this is a risk test more analogous to LDL-cholesterol for cardiovascular risk than a genetic test for Huntington’s disease. For that reason, many physicians will be able to use such tests in clinical practice without a re-education programme or a requirement for genetic counsellors (although the latter group may indeed give support to physicians). The physician is the ideal health care provider to assess and put into context all risk factors as well as to suggest early prevention or detection strategies to their patients, just as they already do today. It is easier to emphasize to physicians that this is a risk test like many other clinical risk factors than to train tens of thousands of genetic counsellors and educate them on how to manage risk factors in patients.

This genetic profile is independent of immediate family history. It is likely that family history will be accounted for by rarer variants of larger effect that have not been found yet. However, this profile already accounts for three times more prostate cancer than family history and has a comparable level of risk. Therefore, this test complements family history by adding another 15% of the population who have twice the risk to the 5% of the population at twofold risk already based on family history alone, making this genetic risk profile the largest risk factor for prostate cancer to date. Together, higher risk patients comprising 20% of the population would account for about 40% of the prostate cancer burden and therefore more aggressive screening of this group could lead to a decrease in prostate cancer morbidity, mortality and the high costs of managing later stage prostate cancer (Fig. 2).

image

Figure 2.  Defining men with higher risk of prostate cancer based on either (i) family history of early prostate cancer alone or (ii) family history or upper 15th percentile of genetic risk based on 25 SNP markers, or both. The genetic risk profile is largely independent of family history – there is 1% overlap on this scale, but not shown. Note that the genetic risk profile defines another 15% of men without family history who have an average relative risk equivalent to that conferred by family history of early prostate cancer.

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Serum PSA and rectal exam screening is recommended by ACS to begin at age 50; however, they recommend earlier PSA screening in higher risk patients. Even more importantly, given the modest sensitivity of PSA for prostate cancer detection when using the conventional cut-off of 4 ng mL–1, high-risk patients with high normal PSA may benefit from a more aggressive evaluation with ultrasound and biopsy rather than watchful waiting or losing the patient to follow-up; this approach is already recommended by NCCN for higher risk patients based on family history and PSA between 2·6 and 4·0 ng mL–1. Adding this important risk factor to PSA evaluation may also improve the specificity of PSA as the prior probability of prostate cancer is much higher in some patients and the genetic test shows no correlation to benign prostatic hyperplasia (BPH), the major source of false-positive PSA elevation. Large clinical utility studies demonstrating the expected increase in PSA specificity and PPV are underway (i.e. higher positive biopsy or repeat biopsy rates in patients with higher genetic risk). Conversely, the patients in the lowest 35 percentile risk have half the risk (average RR of 0·5) and are expected to have a lower positive biopsy rate; therefore, these patients may be managed by watching for PSA rise over time rather than biopsy immediately, saving the health care system 1000–2000 dollars per deferred biopsy. About 80% of prostate biopsies are negative for cancer; more careful risk assessment might decrease the number and cost of invasive procedures in lower risk patients, while leading to higher yields among the higher risk patients.

Genetic risk profiles for the common forms of breast cancer

  1. Top of page
  2. Common variants contributing to common diseases
  3. Multi-marker genetic risk profiles for prostate cancer define risk that is greater than that of family history
  4. Genetic risk profiles for the common forms of breast cancer
  5. Common genetic risk markers for myocardial infarction that are independent of conventional risk factors
  6. Should we wait until we discover all the genetic risk markers before using the validated markers discovered so far?
  7. Should we wait for decade-long randomized clinical trials before using genetic risk profiles for common diseases?
  8. What are the potential harms of screening with genetic risk tests?
  9. Will genetic risk profiles add to conventional risk to improve the cost-effectiveness of our healthcare system?
  10. Should individuals be able to access their genetic information directly?
  11. Disclosures
  12. Address
  13. References

Several common variants have recently been discovered conferring risk of the common forms of breast cancer [22–28]. Rare mutations in the BRCA1 and BRCA2 genes are often measured to define risk in women with strong family history of the early onset form of breast cancer. However, 95% of breast cancers do not fit this pattern – the vast majority of cancer patients do not have family history, much less a family history of early breast cancer. As in prostate cancer, the common variants for breast cancer fit a multiplicative model [29]; the 12 strongest variants define risk of the common forms ranging from 0·4 fold to fourfold risk compared with general population (Fig. 3). Each of these sequence variants have been replicated in 5–25 populations totalling almost 100 000 patients and controls. The upper 5 percentile of the white female population has a twofold risk of the general population and about 0·5% has a threefold risk. Assuming a 12% lifetime risk (SEER database), this translates into a 24–36% lifetime risk, certainly not high enough to trigger prophylactic mastectomies, but high enough to suggest earlier and more intensive screening for the common forms of breast cancer. It is important to note that 5% of women are diagnosed before 40, the age at which mammography is recommended to begin in the US for women who do not have higher risk (20% occur before age 50, the start age of mammography in the UK and recently recommended by the US Preventive Services Task Force amid much controversy!). Most of these women do not have strong family history of breast cancer and are generally negative for BRCA1 and BRCA2 mutations, yet they are not often screened for breast cancer! Nevertheless, for every cancer diagnosed before spread, hundreds of thousands of dollars may be saved in terms of salvage therapy and management of the complications of metastasis.

image

Figure 3.  Common forms of breast cancer risk across the general population based on a genetic risk profile. The 12 validated SNP markers together define relative risks from 0.4 fold to fourfold compared to the general population. The x-axis shows the percentile in the general female population and the y-axis shows the relative risk at each percentile.

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Some women who are considered of average risk based on conventional risk factors will be reclassified as higher risk based on this genetic risk test. Higher risk patients may benefit from earlier screening by mammography and perhaps more intensive screening using breast MRI, which is 2–3 times more sensitive at picking up early breast cancer than mammography alone. ACS currently recommends breast MRI for women with 20% or greater lifetime risk (relative risk of 1·65) on the basis of conventional risk factors and suggests that physicians discuss risks and benefits of screening for women with 15% or more lifetime risk [30]. ASCO recommends chemoprevention with tamoxifen and raloxifene for women with 5-year risk greater than 1·65% based on a Gail score. The current set of markers is independent of the factors used in the Gail score including family history, age at menarche and pregnancy history. Therefore, lifetime and 5-year risk may be better estimated by multiplying the risk from the genetic profile with the independent risk derived from conventional scales.

As in prostate cancer, the negative biopsy rate of women with mammographic images suspicious for cancer is over 80%. Clinical utility studies showing expected improvement in specificity of breast imaging (lower negative biopsies) are ongoing. Conversely, patients with lower risk may have an even greater negative biopsy rate; perhaps a better use of our resources would be deferral of breast biopsy and repeating the mammogram; it costs much less than the 1000–2000 dollar biopsy.

Eight of these 12 variants also determine the likelihood of oestrogen receptor (ER) positive breast cancer vs. ER negative cancer in the event the patient develops cancer [22,24]. These are the first germline markers for the common forms of cancer that predicts future tumour characteristics as opposed to the more traditional somatic changes such as Her2 amplification. Knowing that the woman who is at higher risk for breast cancer is also more likely to have ER positive cancer may further push towards chemoprevention with a SERM like tamoxifen and raloxifene that specifically work to prevent ER positive cancer.

Common genetic risk markers for myocardial infarction that are independent of conventional risk factors

  1. Top of page
  2. Common variants contributing to common diseases
  3. Multi-marker genetic risk profiles for prostate cancer define risk that is greater than that of family history
  4. Genetic risk profiles for the common forms of breast cancer
  5. Common genetic risk markers for myocardial infarction that are independent of conventional risk factors
  6. Should we wait until we discover all the genetic risk markers before using the validated markers discovered so far?
  7. Should we wait for decade-long randomized clinical trials before using genetic risk profiles for common diseases?
  8. What are the potential harms of screening with genetic risk tests?
  9. Will genetic risk profiles add to conventional risk to improve the cost-effectiveness of our healthcare system?
  10. Should individuals be able to access their genetic information directly?
  11. Disclosures
  12. Address
  13. References

The initial four genome-wide association studies of myocardial infarction (MI) and coronary artery disease consistently found only a single location with significant contribution – that within the chromosome 9p21 region near the CDKN2A/B genes [31–33]. About 21% of the general population carries two copies of the risk variants on chromosome 9p21 with 1·6 fold risk compared to the 30% of the population which forms non-carriers. This risk is comparable, both in frequency and in magnitude, to the risk of highest quintile LDL-cholesterol vs. lowest quintile and is independent of conventional risk factors. Recently, we and others have participated in large meta-analyses that discovered several other SNPs of lesser effect associated with MI [34–36]. We have included in our genetic risk test the 9p21 variant and seven other widely replicated markers that are also independent of conventional risk factors such as family history, cholesterol levels, hypertension, diabetes, obesity, smoking history and biomarkers such as c-reactive protein (CRP). These variants have been widely replicated in 20 independent populations totalling over 20 000 patients and 40 000 controls. The overall genetic risk determined by all eight markers ranges from 0·4 to 1·9 compared to the general population and has magnitude and frequency greater than that of LDL-cholesterol and CRP (Fig. 4).

image

Figure 4.  Genetic risk for myocardial infarction across the general population. Markers selected for this eight marker profile only include SNPs that have been shown to confer risk for MI independent of conventional risk factors. These validated markers include a marker in the chromosome 9p21 region and together define relative risks from 0.4 fold to 1.9 fold compared to the general population. The x-axis shows the percentile in the general population and the y-axis shows the relative risk at each percentile.

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Today, patients are often classified into three or four risk categories for next 10-year risk of MI according to the National Cholesterol Educational Program III (ATPIII) guidelines using the Framingham or other risk scales using traditional risk factors. The risk category dictates suggested LDL-cholesterol targets; for example, less than 130 mg dL–1 for intermediate-high risk (10–20% risk) and less than 100 mg dL–1 for high risk (greater than 20%). Two clinical utility studies reported that a 9p21 variant showed a significant association with future MI events independent of other risk factors [37,38]. The marker also reclassified 12–20% of patients into different risk categories that would lead to a change in the recommended LDL target. For example, application of 9p21 variants to the large prospective ARIC cohort by Ballantyne’s group (1350 events in the 10 000 Caucasian patients followed) reclassified about 12% of intermediate and intermediate-high-risk patients into higher or lower risk categories with changed LDL-cholesterol targets [37]. The 15-year prospective study in the Northwick Park Heart Study-II in the UK reclassified 20% of the patients into more informative risk categories [38]. We expect that these reclassification rates will be even higher with the new eight marker profile.

Should we wait until we discover all the genetic risk markers before using the validated markers discovered so far?

  1. Top of page
  2. Common variants contributing to common diseases
  3. Multi-marker genetic risk profiles for prostate cancer define risk that is greater than that of family history
  4. Genetic risk profiles for the common forms of breast cancer
  5. Common genetic risk markers for myocardial infarction that are independent of conventional risk factors
  6. Should we wait until we discover all the genetic risk markers before using the validated markers discovered so far?
  7. Should we wait for decade-long randomized clinical trials before using genetic risk profiles for common diseases?
  8. What are the potential harms of screening with genetic risk tests?
  9. Will genetic risk profiles add to conventional risk to improve the cost-effectiveness of our healthcare system?
  10. Should individuals be able to access their genetic information directly?
  11. Disclosures
  12. Address
  13. References

Some suggest that it is too early to use a genetic risk test for a common disease if we do not yet know all of the sequence variants affecting the risk of that disease [39]. It is true that additional variants will be discovered – the DNA chips used in this generation of GWAS studies only contain common variants and that we are missing rare and intermediate frequency variants as well as structural variants (e.g. copy number variants and inversions) [40]; however, the relative contribution of the many common variants we have discovered vs. less common variants that we have not discovered is necessarily a subject of wide speculation as we have no data to base our assessment on. The hypothesis that a much greater portion of genetic risk for the well studied common diseases remains to be found comes from the fact that only a small portion of sibling recurrence risk is explained by the common variants. However, as we have reported through our work using our comprehensive medical and genealogical databases, excess familiality seen in common disease extends far beyond the nuclear family – indeed, much of tight familial clustering seen only in a small portion of the cases may be largely driven by rare variants with a strong effect, while much of the genetic component of risk for most individuals who do not have close family history of the disease may be attributable to common genetic variants. The confluence of many common risk alleles of modest effect in some individuals confers high risk.

The current genetic profiles can reclassify as higher risk a substantial portion of patients thought to be at average risk based on conventional factors. Waiting until we completely understand 100% of the genetic risk before using what we do know for risk stratification would be analogous to not measuring risk factors like LDL and CRP for cardiovascular disease because of the fear that future biomarkers may reclassify a higher risk patient today as average risk tomorrow. In medicine, we generally apply risk factors as we discover and validate them, if they are clinically useful for the individual patient.

Ransokoff and Khoury cite recent analyses that raise concerns about the accuracy of genetic profiling. One critique compared one direct-to-consumer company with another and found disparities between the results reported for diseases in common [41]. However, they failed to point out that these companies use very different numbers of markers to define risk and that neither one has kept up with the discoveries and validations that we and others report in the literature. Our company is a diagnostic company and our genetic profiles in both our individual disease risk tests and our more comprehensive offering, deCODEme, are regularly updated with batches of new validated markers. Ransokoff and Khoury incorrectly interpret another study looking at successive addition of genetic markers as showing ‘significant reclassification of type 2 diabetes from high risk to low risk and vice versa’ [42]. That analysis defined high risk as anyone with risk greater than 1·0 and low risk as less than 1·0, so even a subtle change from 0·95 to 1·05 relative risk would be counted as a ‘significant change’ in risk. However, our profiles are updated with batches of markers and as expected, it is uncommon to have someone change, for example, from higher risk greater than 2·0 to lower risk less than 0·5. Indeed, in the cited study, only 6% of the higher risk group that was homozygous for the risk variant in TCF7L2, the strongest genetic risk factor for type 2 diabetes, changed to below 1·0 risk when 17 other genetic markers were added. Risk assessments, of course, do ‘evolve’ in medicine as additional markers are validated and used (e.g. total cholesterol, vs. LDL and HDL cholesterol) and genetic profiles will do so as well further improving the accuracy of overall risk assessment including conventional risk factors.

Should we wait for decade-long randomized clinical trials before using genetic risk profiles for common diseases?

  1. Top of page
  2. Common variants contributing to common diseases
  3. Multi-marker genetic risk profiles for prostate cancer define risk that is greater than that of family history
  4. Genetic risk profiles for the common forms of breast cancer
  5. Common genetic risk markers for myocardial infarction that are independent of conventional risk factors
  6. Should we wait until we discover all the genetic risk markers before using the validated markers discovered so far?
  7. Should we wait for decade-long randomized clinical trials before using genetic risk profiles for common diseases?
  8. What are the potential harms of screening with genetic risk tests?
  9. Will genetic risk profiles add to conventional risk to improve the cost-effectiveness of our healthcare system?
  10. Should individuals be able to access their genetic information directly?
  11. Disclosures
  12. Address
  13. References

The authors of the companion piece suggest that although many of these markers have been replicated as common risk factors in tens of thousands of patients and tens of thousands of controls in both retrospective and prospective studies, we should wait until randomized clinical trials are designed and run to compare the long-term (10 years or greater) morbidity and mortality outcomes of tens of thousands of patients managed with information from both the genetic factors and traditional risk factors vs. tens of thousands of patients managed using only traditional risk factors. Others believe that more focused clinical utility studies can be designed to demonstrate retrospectively or prospectively how the genetic markers improve specificity of conventional screening tests (such as breast imaging and PSA as mentioned above) to improve our targeting of limited healthcare resources. We agree that continuing and expanding clinical utility studies to further define the evidence and clinical indications are important to further support and define appropriate use of genetic risk tests as is done for any other diagnostic test after launch [43]. It should be pointed out with rare exceptions, no risk test or diagnostic test has been run in randomized clinical trials looking out for mortality outcomes before launch or even before FDA approval (which only covers analytical and clinical validity, not utility). In almost all cases, clinical utility studies, usually in the form of observational studies and rarely as RCTs, were run only after the profession developed substantial experience integrating them into practice. Examples include mammography, breast MRI, brain MRI and C-reactive protein. The later studies helped to define further the magnitude of the benefits over potential harms.

What are the potential harms of screening with genetic risk tests?

  1. Top of page
  2. Common variants contributing to common diseases
  3. Multi-marker genetic risk profiles for prostate cancer define risk that is greater than that of family history
  4. Genetic risk profiles for the common forms of breast cancer
  5. Common genetic risk markers for myocardial infarction that are independent of conventional risk factors
  6. Should we wait until we discover all the genetic risk markers before using the validated markers discovered so far?
  7. Should we wait for decade-long randomized clinical trials before using genetic risk profiles for common diseases?
  8. What are the potential harms of screening with genetic risk tests?
  9. Will genetic risk profiles add to conventional risk to improve the cost-effectiveness of our healthcare system?
  10. Should individuals be able to access their genetic information directly?
  11. Disclosures
  12. Address
  13. References

Ransokoff and Khoury write persuasively that there may be several potential harms that can come from genetic risk tests. Furthermore, they insist that this harm should always be less than the more obvious benefit that can result in defining higher risk patients who can be put onto the path of prevention, earlier detection and earlier treatment. However, for decades, there has indeed been widespread concern that genetic labelling can lead to discrimination and counterproductive behaviours. Federal and state regulations have successfully reduced the potential of discrimination including recent HIPAA and GINA legislation. Second, the recently reported REVEAL study showed that patients tested and given their results for the strongest known risk factor for Alzheimer’s disease, the ApoE4 allele, did not have significantly different rates of distress, depression, or anxiety from those who were not given their results [44]. Finally, Ransokoff and Khoury fail to cite any studies that show that it is dangerous for people to receive their results of genetic risk assessment for common diseases.

We agree with Ransokoff and Khoury that medicine should maintain its high standard of showing that the benefits of new drugs outweigh potential harms – a drug is designed to change physiology and unexpected consequences need to be determined in thousands of humans before a drug is launched for widespread use. However, we maintain that genetic risk tests for common diseases are not determinative or diagnostic of a particular disease – instead, when used together with conventional risk factors, they help make a more accurate determination of the overall risk. Medicine has several risk-based guidelines where patients who exceed certain risk thresholds are special: they get earlier or more intensive screening with more definitive diagnostics or a preventive strategy (behavioural or therapeutic). As they correctly point out, genetic tests are just like any other clinical tests, helping physicians to define overall risk more accurately.

In their discussion of prostate cancer screening trials Ransokoff and Khoury focus more on the side effects of treatment than the significant reduction of death (20–27%) found in the European Prostate Screening Trial; the authors unfairly characterize that the results of this study ‘show that benefit of screening is low at best, if it exists at all’. Note that prostate cancer screening is a means to ultimately decide who receives the more definitive diagnostic test-prostate biopsy. Once a diagnosis of high grade or intermediate grade cancer is made, then patient and physician can weigh the relative harms of incontinence and impotence (much of which can be managed) vs. early death and painful metastases (which largely cannot be managed), especially in men younger than 70 at diagnosis.

In our opinion, there is greater potential harm done when more intensive diagnostic testing or prevention strategies are withheld from patients who are at higher risk and they and their physician do not know it until the patient presents in an advanced stage of cancer or after substantial myocardium or cerebral cortex is lost. Conversely, there are additional potential harms to patients who receive unnecessary diagnostic tests despite being at a lower risk, but their physician does not know it. Therefore, although they are concerned that genetic testing would lead to an overutilization of healthcare resources, we think it is likely that it will lead to a smarter, more appropriate use of resources – fewer resources for lower risk patients balancing greater diagnostic yields for higher risk patients. Cost savings come from both ends of the spectrum: lower screening costs at lower risk end and earlier detection and prevention on the higher risk end.

Will genetic risk profiles add to conventional risk to improve the cost-effectiveness of our healthcare system?

  1. Top of page
  2. Common variants contributing to common diseases
  3. Multi-marker genetic risk profiles for prostate cancer define risk that is greater than that of family history
  4. Genetic risk profiles for the common forms of breast cancer
  5. Common genetic risk markers for myocardial infarction that are independent of conventional risk factors
  6. Should we wait until we discover all the genetic risk markers before using the validated markers discovered so far?
  7. Should we wait for decade-long randomized clinical trials before using genetic risk profiles for common diseases?
  8. What are the potential harms of screening with genetic risk tests?
  9. Will genetic risk profiles add to conventional risk to improve the cost-effectiveness of our healthcare system?
  10. Should individuals be able to access their genetic information directly?
  11. Disclosures
  12. Address
  13. References

While our health care system struggles with major issues of the cost of expensive therapies and long-term palliative courses for later stage cancer patients and survivors of cardiovascular and cerebrovascular events, it is particularly illuminating to realize that less than 5% of the health care dollar is used for diagnostics with most of the remainder allocated to treatment. Moving just a small portion of the downstream therapeutic costs to the diagnostics column to identify and manage higher risk patients, may shift the curve from late-stage intervention to earlier detection and prevention with dramatic savings in costs and lives. Genetic risk tests offer one important methodology that is the foundation of more cost-effective personalized medicine rather than continuing the highly inefficient status quo of one-size fits all. While we will continue to discover additional markers to improve further the predictability of these genetic tests, many of the current risk profiles represent relative risk that matches or exceeds the risk of conventional risk factors. Their utility is the determination of the risk and what you as a physician will do differently with some of your patients who change risk categories. Therefore, many of these genetic risk tests are ready for prime time now.

Should individuals be able to access their genetic information directly?

  1. Top of page
  2. Common variants contributing to common diseases
  3. Multi-marker genetic risk profiles for prostate cancer define risk that is greater than that of family history
  4. Genetic risk profiles for the common forms of breast cancer
  5. Common genetic risk markers for myocardial infarction that are independent of conventional risk factors
  6. Should we wait until we discover all the genetic risk markers before using the validated markers discovered so far?
  7. Should we wait for decade-long randomized clinical trials before using genetic risk profiles for common diseases?
  8. What are the potential harms of screening with genetic risk tests?
  9. Will genetic risk profiles add to conventional risk to improve the cost-effectiveness of our healthcare system?
  10. Should individuals be able to access their genetic information directly?
  11. Disclosures
  12. Address
  13. References

Over the past decade or so there has been a substantial change in the behaviour of the consumers of healthcare. Today, there is hardly a patient between the ages of 15 and 70 who goes to see a physician for a new condition without having downloaded from the internet large amount of information on their condition. It could be argued, thereby, that consumers of healthcare are taking more control of their own affairs. Access to information about the genetic risk of diseases would allow this development to proceed to the next level. The man who knows the nature of his disease is more likely to seek appropriate help to treat it and by the same logic, a man who knows the risk he has of developing a disease is more likely to seek help to mitigate the risk. It is also important to recognize that by learning about the genetic risk you have of diseases, you are simply learning certain aspects about who you are. One of the assumptions of our culture is that is always helpful to learn in more detail who you are. It is important that people can access this information without having to go through a healthcare professional because such an intermediary could serve as a barrier. Furthermore, there is no evidence in support of the notion that knowing your genetic risk of common diseases is harmful.

References

  1. Top of page
  2. Common variants contributing to common diseases
  3. Multi-marker genetic risk profiles for prostate cancer define risk that is greater than that of family history
  4. Genetic risk profiles for the common forms of breast cancer
  5. Common genetic risk markers for myocardial infarction that are independent of conventional risk factors
  6. Should we wait until we discover all the genetic risk markers before using the validated markers discovered so far?
  7. Should we wait for decade-long randomized clinical trials before using genetic risk profiles for common diseases?
  8. What are the potential harms of screening with genetic risk tests?
  9. Will genetic risk profiles add to conventional risk to improve the cost-effectiveness of our healthcare system?
  10. Should individuals be able to access their genetic information directly?
  11. Disclosures
  12. Address
  13. References