Ian Grady MD, Editorial, June 2017
We now live in an era in which most of the cancers that affect humanity are preventable. Lung cancers through smoking cessation, cervical cancers through vaccination, colon through polypectomy, and many skin cancers through decreased sun exposure. For other cancers, such as breast, control through screening has brought significant reductions in mortality, cost of treatment, and the vast burden of human suffering caused by these diseases.
While most cancers occur spontaneously, cancers related to genetic cancer susceptibility may account for up to 25% new diagnoses.(1)
Identification of susceptibility mutations facilitates at least early detection and, in many cases, primary cancer prevention. This is particularly true of breast and gynecologic cancers. Consequently, the detection of a susceptibility mutation only after a cancer is diagnosed is a failure of preventive medicine.
Next generation gene sequencing has greatly reduced the cost of detecting susceptibility mutations, while increasing the number of genes that can be sequenced. In addition, public awareness of genetic susceptibility has grown significantly over the last two decades. All of this is resulting in huge increases in genetic sequencing and in the amount of genetic data that clinicians need to analyze.
The Diagnostic Model
Traditionally, individuals who meet specified, and often very complex, criteria are referred to genetic counselors who counsel the patients and decide if gene sequencing is appropriate. Testing, if performed, is then followed by post-test counseling. Other family members can be similarly evaluated if a mutation is identified.
This is a diagnostic model. An abnormality is identified. Then a work-up is performed to evaluate the abnormality for a genetic basis. This approach is advocated by a variety of professional groups.(1, 2) It is very similar to the approach used in breast cancer control prior to the widespread use of mammographic screening.
The main problem with the diagnostic approach is that large numbers of actionable susceptibility mutations are missed.(3)Â Commonly used models to predict mutation risk based on family history perform poorly, especially in families with a small number of individuals.(4) Moreover, studies performed in Ashkenazim, a high mutation prevalence population, show that up to 50% of deleterious BRCA1 and BRCA2 mutation carriers have no family history.(5, 6)
Screening for Susceptibility Mutations
The failure of diagnostic evaluation based on family history, more than any other factor, has led to the development of screening-based models for susceptibility mutation detection. The idea here, rather than relying on family history as a trigger for testing, is to simply to perform sequencing over a broad range of cancer susceptibility genes for the population – at an early enough age that risk-reducing interventions can take place before the carrier develops the disease.
There are good examples of successful screening programs for specific diseases in limited populations such as Tay-Sachs Disease, Cystic Fibrosis, and Factor V Leiden. The closest example to a population-based cancer susceptibility screening program in the developed world is the screening of neonates for metabolic diseases. This has been successfully performed in the United States since the 1960s.(3)
Concerns have been raised about potential long-term negative effects of genetic knowledge on the populations that would be served by a screening program. These include anxiety in deleterious mutation carriers and false reassurance in non-mutation carriers leading to avoidance of recommended screening. There is also the possibility of clinician misinterpretation of testing results, particularly variants of uncertain significance, leading to inappropriate and unnecessary preventive treatment.(1, 7)
Screening for BRCA1 and BRCA2 susceptibility mutations has been studied among Ashkenazim, in Israel, the United States, and Australia.(5, 6, 8) These studies address the questions above through different mechanisms and provide a model on which an effective cancer susceptibility screening program can be based.
The Changing Role of the Genetic Counselor
In the traditional diagnostic model, the genetics counselor decides not only what sequencing, if any, is performed, but when and how. They also inform their client about the benefits and risk of testing. In a screening program, these decisions are made in advance, since the great majority of patients will not be seeing a genetics counselor prior to sequencing.
The issue here is simply one of manpower. There are currently 4,140 certified genetic counselors practicing in the United States. About one-third of these are cancer genetic counselors.(1) That works out to about one cancer genetic counselor (CGC) per every 233,000 people.
The National Society of Genetic Counselors hopes to have 1 CGC in practice for every 100,000 people in practice within five years.(1) The population of the U.S in five years will be 338 million, so there will need to be an additional 3400 â€“ roughly triple the current number â€“ CGCs in practice within five years to meet this goal.(9)
Even if tripling the CGC manpower level in five years was possible, it wouldn’t matter. Assuming that we start a United States National Screening Program today, by 2022, it will be sequencing more than 4.5 million individuals per year.(9) If you include visits for both pre-test and post-test counseling, you are talking about at least 9 million client encounters per year. Â That, of course, is in addition to the non-screening CGC workload. The screening workload would be even higher in the first one to two years of the program, since the program will be initially sequencing a much broader age range.
Genetic counselors will, of course, have a vital and pivotal role to play in a screening program. But they will not be diagnosticians. They will be researchers, educators, and consultants for the clinicians who are ordering and interpreting the results.
Implementation of a Screening Program
Mary-Claire King, who first documented the BRCA1 and 2 gene inheritance pattern, has recommended screening the entire female population at age 30 for BRCA1 and BRCA2 stop codon mutations.(8) In spite of the shocked reaction in the traditional genetic testing community, this was a modest proposal.
The trend in clinical practice is to sequence with increasingly broad multi-gene panels.(11) The broader the panel, the more variants will be obtained. More importantly, there are almost certainly mutations in genes that confer cancer susceptibility that we have not yet identified. This raises the possibility that individuals might have to be screened again in a few years as technology advances. Of course, eventually we will completely sequence every gene in everyone, but this will not happen for several years.
To start, it would be best to sequence the broadest range of genes that are commercially available. Yes, there will be a lot of variants. But this will minimize the need to have to retest people in the future, which would be expensive. The National Cancer Genetic Screening Program will meet the variant management challenge with explicit guidelines.
Patient education and counseling solutions will be included. In screening studies performed in Israel, pre-test and post-test counseling is provided through written material. This is very well accepted by the participants.(6)
People found to have deleterious mutations respond with appropriate risk-reduction behaviors and do not experience long-term anxiety. People who do not carry deleterious mutations also respond well. Avoidance of appropriate healthcare intervention such as routine screening was not seen in this population.(6)
The Role of Industry
In addition to collecting specimens, sequencing, and reporting results, industry must continue to support the clinicians who are interpreting test results and educating those screened. Industry and established health care systems must collaborate to provide the necessary IT infrastructure. Industry must also support the evolution of sophisticated tools such as ASK2ME.org to power informed decision-management as information about the expanding list of susceptibility mutations exceeds human capacities.
The significance of deleterious mutations and variants will continue to be worked out by industry and the medical community and reported to the clinicians. A number of companies provide genetic counselors to both clinicians and the public now and this service will grow significantly with a screening program.
Testing companies will need to cooperate more than ever before. If one company learns something regarding a mutation or a variant, then that information will have to be shared. Moreover, companies will have to track a vast number of variants so that carriers can be notified, through their primary care providers, if a variant is reclassified.
The Role of Government
Legal protections regarding the use of genetic information will have to be safeguarded and strengthened. Although protection is provided through the Federal Genetic Information Nondiscrimination Act and the Affordable Care Act, this protection is incomplete.(12) Fear of genetic discrimination is one of the principal reasons why people refuse gene sequencing.
The use of genetic information must not be used to deny employment, educational opportunities, insurance coverage, access to capital, or access to healthcare. Genetic status must never be allowed to be a preexisting condition.
Government payers will also need to approve genetic screening as a covered expense for Medicare and Medicaid patients. Legislation that mandates private insurance coverage may also be required. In addition, legislation that mandates the sharing of information regarding deleterious mutations and variants among testing companies may be required.
The Role of the Primary Care Provider
The primary care provider, including family practitioners, internists, gynecologists, surgeons, and various allied health professionals will be the providers who interact directly with those screened. Pre-test counseling and post-test interpretation of results will be performed by these clinicians.
They will depend heavily on industry support to determine the significance of results, particularly variants. Genetic counselors and other genetics professionals will be their consultants.
Education of the primary care providers will be crucial to the success of the program. They will need to understand the importance of susceptibility screening for their clients and be able to explain results.
Research to Support Population-Based Screening
Research is needed to support a large-scale susceptibility screening program. The true incidence of many deleterious mutations is not known in the US population. A better understanding of incidence would help to develop faster and less expensive screening tests.
A Better Future
A national cancer susceptibility screening program is within reach. Potential reductions in mortality, cost of cancer care, and human suffering will follow. Â No new technology is needed. We can use what we have.
It will require effort, capital, and cooperation from health care providers, genetics professionals, payers, and the government, but we can do this.
For Further Reading
1. Haidle JL. The Challenge of the VUS.Â American Society of Breast Surgeons 18th Annual Meeting; Las Vegas, NV 2017.
2. Moyer VA, on behalf of the USPSTF. Risk assessment, genetic counseling, and genetic testing for brca-related cancer in women: U.S. preventive services task force recommendation statement. Annals of Internal Medicine. 2014;160(4):271-81. doi: 10.7326/M13-2747.
3. Foulkes WD, Knoppers BM, Turnbull C. Population genetic testing for cancer susceptibility: founder mutations to genomes. Nat Rev Clin Oncol. 2016;13(1):41-54. doi: 10.1038/nrclinonc.2015.173.
4. Weitzel JN, Lagos VI, Cullinane CA, et al. Limited family structure and brca gene mutation status in single cases of breast cancer. JAMA. 2007;297(23):2587-95. doi: 10.1001/jama.297.23.2587.
5. Gabai-Kapara E, Lahad A, Kaufman B, Friedman E, Segev S, Renbaum P, et al. Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2. Proceedings of the National Academy of Sciences. 2014;111(39):14205-10.
6. Lieberman S. BRCA1/BRCA2 population screening in Ashkenazi Jews: Long term impact.Â European Society of Human Genetics; Copenhagen, Denmark 2017.
7. Kurian AW, Li Y, Hamilton AS, Ward KC, Hawley ST, Morrow M, et al. Gaps in Incorporating Germline Genetic Testing Into Treatment Decision-Making for Early-Stage Breast Cancer. Journal of Clinical Oncology. 2017:JCO.2016.71.6480. doi: 10.1200/JCO.2016.71.6480.
8. King M, Levy-Lahad E, Lahad A. Population-based screening for brca1 and brca2: 2014 lasker award. JAMA. 2014;312(11):1091-2. doi: 10.1001/jama.2014.12483.
9. Btlas. Population Pyramids of the World from 1950 to 2100Â [cited 2017]. Available from: https://www.populationpyramid.net/.
10. Khoury MJ, McCabe LL, McCabe ERB. Population Screening in the Age of Genomic Medicine. New England Journal of Medicine. 2003;348(1):50-8. doi: 10.1056/NEJMra013182.
11. LaDuca H, Stuenkel AJ, Dolinsky JS, Keiles S, Tandy S, Pesaran T, et al. Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients. Genet Med. 2014;16(11):830-7. doi: 10.1038/gim.2014.40.
12. Green RC, Lautenbach D, McGuire AL. GINA, Genetic Discrimination, and Genomic Medicine. New England Journal of Medicine. 2015;372(5):397-9. doi: 10.1056/NEJMp1404776.