Population-based Cancer Genetic Testing - Are We There Yet?

Population-based Cancer Genetic Testing-Are We There Yet?

It is estimated that 1-3% of the general population in the United States carry a genetic mutation for a common hereditary condition and do not know it.¹ This supports a twist on the common catch phrase: “What you don’t know can hurt you”.

Paradigm Shift-Where we are headed!

Population genetic testing is defined as the process of offering genetic testing for common hereditary conditions to healthy individuals in the population who may carry a genetic mutation that predisposes them to certain conditions, including cancer.² It has been suggested that population genetic testing may have a significant impact on reducing morbidity and mortality from hereditary cancers by identifying those at a high risk for developing cancers known to be associated with certain genetic mutations through targeted screening and prevention measures.

Population genetic testing would represent a paradigm shift in practice to offer genetic testing to healthy, unaffected individuals regardless of personal or family history of cancer before a cancer diagnosis occurs, which is the main goal of cancer genetic testing. It has been proposed that genetic testing could be initially offered to young adults, starting around 25-30 years of age through a genetic counseling appointment with a genetic professional to provide comprehensive information and allow the individual to provide informed consent to the testing. The individual would be offered genetic testing of only actionable cancer genes where the associated cancer risks are well defined and there are established screening and/or prevention options to manage the risk. For a list of clinically actionable genes identified by the American College of Medical Genetics (ACMG) click here.

Current Approach-Where we have been.

The current approach and national guidelines for cancer genetic testing is based on personal and/or family history of cancer according to criteria detailed by national organizations such as the National Comprehensive Cancer Network (NCCN) and the American Society of Clinical Oncology (ASCO) and the ACMG, to name a few of the main ones. These guidelines are acted upon only once one or more cancer diagnoses have occurred in the family. Studies have shown that more than half of the individuals identified with carrying a mutation did not meet current national guidelines for a referral for cancer genetic counseling and testing.³ For more details related to these statistics, see this MEDPAGE Today article titled Many With Cancer Predisposition Diseases Unaware of Genetic Status— Moreover, a significant proportion do not qualify for genetic screening under current guidelines.

Pros and Cons

Several studies have been completed to evaluate the public’s view of population genetic testing.^4-9 Some of the identified barriers have included personal levels of anxiety, identifying risk to one’s children, privacy and insurance discrimination concerns and worry about screening procedure results.

Results of additional studies identified support of population genetic testing which included the potential in reduction of morbidity and mortality of cancer, the ability to prepare for the future, and the use of the results for pharmacogenomics. Study results showed that the usefulness of population genetic testing is to identify those at highest risk for cancer enabling the individual to adopt a heightened and targeted screening and preventions plan and to reduce cancer incidence, morbidity and mortality. In additional, health care dollars are better utilized through the identification of those who would most benefit from screening and prevention measures.^10-12

The field of cancer genetics is advancing at a rapid pace with technology improvements which have reduced the cost of sequencing significantly. Cancer genetics is playing a big role in personalized/precision medicine in many aspects of care, not just cancer, but also in cardiology, maternal fetal health, neurology and pharmacogenomics. The current direct cost for genetic testing of actional cancer genes is $250. Click here for additional cost details from Invitae, a national CLIA approved genetics lab in San Francisco, California. There are defined screening recommendations and some prevention measures established for each of the actionable genes if a mutation is identified. Therefore, if a mutation is identified, medical insurance providers provide coverage for the screening and prevention measures. 

Hurdles to Jump

Some of the conflicts associated with implementing population genetic testing is that some healthcare providers do not feel they have enough education or background to offer cancer genetic testing to their patients.^{9, 13} In addition, some also did not fully recognize the utility or usefulness of the genetic testing.

Another barrier of implementing population genetic testing is the limited number of cancer genetic professionals to provide the counseling and testing services. Alternative delivery methods of cancer genetic information will need to be developed and utilized, such as ChatBots, artificial intelligence programs with risk stratification features. Once an individual has received adequate information to provide informed consent to the testing, genetic testing could be streamlined and coordinated through commercial CLIA-approved laboratories. Anyone who is found to carry a cancer genetic mutation will be required to meet with a cancer genetic professional for a full discussion of their result, how to manage and mitigate their cancer risk and the opportunity to offer cascade genetic testing to bloodline relatives such as their children, siblings and others.  

Key Pilot Studies

The current status of population genetic testing is in the research stage through pilot and feasibility studies. A current ongoing study, BabySeq is expected to provide valuable information related to incidental genetic findings of cancer genetic mutations that are part of the study. More information can be found here.  The figure below represents potential results from the BabySeq study.

Mary-Claire King, PhD headed up a study of population-based genetic testing of BRCA1 and BRCA2, the two main hereditary breast cancer genes, in the Ashkenazi Jewish population in Israel.¹⁴ Men were selected for the screening to prevent selection bias and allowing female mutation carriers to be identified only by relationship to a male carrier in the family. The study identified 175 male carriers of a BRCA1 or BRCA2 mutation which led to the option of all female relatives to be tested for the identified mutation. Women who were found to carry a BRCA1 mutation had a very high lifetime risk for developing breast and ovarian cancer, approaching 76-83% for developing breast or ovarian cancer by age 80. Dr. King made the bold statement that to identify a woman as a carrier only after she develops cancer is a failure of cancer prevention.¹⁵

Impact Potential

The identification of those at the highest risk for developing certain cancers is paramount to cancer prevention efforts. These individuals would have the option to partake in heightened, targeted screenings for early detection and preventive measures to detect cancer at a very early stage or avoid a cancer diagnosis altogether.

Additional pilot and feasibility studies are needed to measure the impact and acceptance of population-based genetic testing in a healthy population not selected based on personal or family history of cancer. Long term studies are also needed to determine the real impact on the reduction of cancer diagnoses or the identification of cancers at an early stage. Additional studies are needed to assess and measure the actions taken by those who tested positive for a mutation. Did they follow through with high-risk screening measures on a consistent basis throughout their life? Or, did they choose preventive surgical options and if so, what was the long-term outcome of their decision?

Population-based cancer genetic testing offers many benefits to individuals in the United States who are ready and prepared to learn their genetic status and feel empowered to take action to mitigate their predisposition genetic risk, a risk that was already determined at the time of their own conception.

 

References

 

1. Murray M. F., Evans J. P., Angrist M., Chan K., Uhlmann W. R., Doyle D. L., et al. (2018). A Proposed Approach for Implementing Genomics-Based Screening Programs for Healthy Adults. Washington, DC: NAM Perspectives.
2. Shen, E. C., Srinivasan, S., Passero, L. E., Allen, C. G., Dixon, M., Foss, K., Halliburton, B., Milko, L. V., Smit, A. K., Carlson, R., & Roberts, M. C. (2022). Barriers and Facilitators for Population Genetic Screening in Healthy Populations: A Systematic Review. Frontiers in genetics, 13, 865384.
3. Beitsch, P. D., Whitworth, P. W., Hughes, K., Patel, R., Rosen, B., Compagnoni, G., Baron, P., Simmons, R., Smith, L. A., Grady, I., Kinney, M., Coomer, C., Barbosa, K., Holmes, D. R., Brown, E., Gold, L., Clark, P., Riley, L., Lyons, S., Ruiz, A., … Nussbaum, R. L. (2019). Underdiagnosis of Hereditary Breast Cancer: Are Genetic Testing Guidelines a Tool or an Obstacle?. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 37(6), 453–460.
4. Hardie E. A. (2011). Australian Community Responses to the Use of Genetic Testing for Personalised Health Promotion. Aust. J. Psychol. 63, 119–129.
5. Nusbaum R., Leventhal K.-G., Hooker G. W., Peshkin B. N., Butrick M., Salehizadeh Y., et al. (2013). Translational Genomic Research: Protocol Development and Initial Outcomes Following SNP Testing for Colon Cancer Risk. Transl. Behav. Med. 3, 17–29.
6. Rubinsak L. A., Kleinman A., Quillin J., Gordon S. W., Sullivan S. A., Sutton A. L., et al. (2019). Awareness and Acceptability of Population-Based Screening for Pathogenic BRCA Variants: Do Race and Ethnicity Matter? Gynecol. Oncol. 154, 383–387. 
7. Henneman L., Timmermans D. R., Bouwman C. M., Cornel M. C., Meijers-Heijboer H. (2011). A Low Risk Is Still a Risk”: Exploring Women’s Attitudes towards Genetic Testing for Breast Cancer Susceptibility in Order to Target Disease Prevention. Public Health Genomics 14, 238–247. 
8. Sanderson S. C., Linderman M. D., Suckiel S. A., Diaz G. A., Zinberg R. E., Ferryman K., et al. (2016). Motivations, Concerns and Preferences of Personal Genome Sequencing Research Participants: Baseline Findings from the HealthSeq Project. Eur. J. Hum. Genet. 24, 14–20.
9. Joshi E., Mighton C., Clausen M., Casalino S., Kim T. H. M., Kowal C., et al. (2020). Primary Care Provider Perspectives on Using Genomic Sequencing in the Care of Healthy Children. Eur. J. Hum. Genet. 28, 551–557.
10. Hay J. L., Kaphingst K. A., Buller D., Schofield E., Meyer White K., Sussman A., et al. (2021). Behavioral and Psychological Outcomes Associated with Skin Cancer Genetic Testing in Albuquerque Primary Care. Cancers 13, 4053.
11. Lacson J. C. A., Doyle S. H., Qian L., Del Rio J., Forgas S. M., Valavanis S., et al. (2021). A Randomized Trial of Precision Prevention Materials to Improve Primary and Secondary Melanoma Prevention Activities Among Individuals with Limited Melanoma Risk Phenotypes. Cancers 13, 3143.
12. Smit A. K., Allen M., Beswick B., Butow P., Dawkins H., Dobbinson S. J., et al. (2021). Impact of Personal Genomic Risk Information on Melanoma Prevention Behaviors and Psychological Outcomes: a Randomized Controlled Trial. Genet. Med. Off. J. Am. Coll. Med. Genet. 23, 2394–2403.
13. Vassy J. L., Christensen K. D., Slashinski M. J., Lautenbach D., Robinson J. O., Blumenthal-Barby J. A., et al. (2014). Someday it Will Be the Norm”: Physician Perceptions of the Clinical Utility of Whole Genome Sequencing. J. Gen. Intern. Med. 29, S4.
14. Gabai-Kapara, E., Lahad, A., Kaufman, B., Friedman, E., Segev, S., Renbaum, P., Beeri, R., Gal, M., Grinshpun-Cohen, J., Djemal, K., Mandell, J. B., Lee, M. K., Beller, U., Catane, R., King, M. C., & Levy-Lahad, E. (2014). Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2. Proceedings of the National Academy of Sciences of the United States of America, 111(39), 14205–14210.
15. King, M. C., Levy-Lahad, E., & Lahad, A. (2014). Population-based screening for BRCA1 and BRCA2: 2014 Lasker Award. JAMA, 312(11), 1091–1092.