Universal germline genetic testing of individuals with cancer

Samantha Greenberg

PhD Student, College of Nursing

April 6th 2021

Rapid changes in genomics increase accessibility and affordability

The Human Genome Project kicked off in 1990, sparking a decade of revolutionary genetic science¹. During the discovery of ~22,000 genes, BRCA1 and BRCA2 were identified as two genes associated with hereditary breast cancer^2,3. Notably, pathogenic variants, or mutations, in these genes, put individuals at increased risk for breast and ovarian cancer among other cancer types⁴. The technology was costly, where sequencing of a genome cost over 10 million dollars. While BRCA testing was not millions of dollars, it was often over a thousand dollars out of pocket after insurance had paid their portion. Gene sequencing was then complemented by deletion/duplication analysis, and later usurped by next generation sequencing, sending the cost of testing plummeting⁵. As a result, comprehensive germline testing is recommended for individuals who had previous genetic testing prior to 2013, when the Supreme Court lifted restrictions on Myriad Genetics’ BRCA patent, and multi-gene panel testing became the new gold standard of care⁶.

As prices fall and growing evidence suggests individuals with germline pathogenic variants may be missed by current guidelines, there is a rising question: Should we stick to guidelines, or consider universal germline genetic testing in all individuals with cancer?

The argument for maintaining guidelines-based genetic testing

For decades, the National Comprehensive Cancer Network has been the leader in cancer treatment, prevention, and screening guidelines for the oncology community^7,8. Comprised of experts from designated comprehensive cancer centers by the National Cancer Institute, bi-annual panels review the newest literature and adjust guidelines based on evidence-based research. In the germline genetic testing realm, guidelines are set both by genetics committees, as well as individual cancer type panels that determine who benefits from germline genetic testing. Evolving alongside new research, these expert panels evaluate the cost and benefit of germline genetic testing in patients. As of now, guidelines are still based on personal and family history, though the past few years have brought new criteria. Specifically, individuals with somatic tumor testing that identifies a BRCA1/2 variant benefit from germline testing regardless of tumor type due to the high rate of concordance with germline mutations⁹.

The argument for the continuation of reliance on guidelines for germline testing in individuals with cancer is based on the potential downstream impact of widespread genetic testing. Genetic information is sensitive, and has previously been considered to need a ‘gatekeeper’. It is only in the last few years that direct-to-consumer comprehensive cancer genetic testing has become available without a formal visit with an ordering provider. Furthermore, concerns for psychosocial and familial impact of a mutation, or a variant of uncertain significance, may fuel some of the resistance to wider spread testing^10,11.

Why universal genetic testing is warranted

Though data guides decision making, it is the ancedotes that help frame the argument for universal genetic testing. Often an individual comes in with a history of breast cancer and a BRCA2 mutation they got through direct-to-consumer testing and no one had mentioned genetic testing in the previous 60 years of their life. This means we are missing people who could be undergoing preventative measures to reduce cancer mortality.

This is reflected in the literature. In individuals with prostate cancer, 37% of individuals with germline mutations did not meet clinical criteria¹². This is the same in breast cancer, where nearly half of patients with breast cancer and a mutation would have been missed by current testing guidelines¹³. Recently, guidelines expanded to recommend germline testing in all pancreatic adenocarcinoma after limited criteria missed germline mutations in only those with cancer and a known family history¹⁴. A study of individuals with solid tumors found that 192 patients (6.4% of the sample) had clinically actionable mutations that would have been missed by guidelines¹⁵. Furthermore, as somatic testing evolves, incidental findings that have allele frequencies aligned with inherited germline variants rather than tumor-specific markers are identified, sparking a need for oncologist education¹⁶. As testing costs continue to fall, the future seems inevitable: in the near future, we will offer germline testing to all individuals with cancer.

What needs to be figured out for widespread acceptance of universal genetic testing

Germline genetic testing is not a simple thing to be thrown into standard of practice. Patients benefit from pre-test education from a genetic counselor or their clinician to understand the personal, familial, and societal impact of their genetic test before they consent to testing¹⁷. Genetic counselor supply is a frequently highlighted topic¹⁸. If we drastically expand the population who needs genetic testing, will there be enough clinicians to provide this pre-test education? Do oncologists feel comfortable educating patients on potential outcomes? Research suggests the jury is out, and additional studies are needed to identify appropriate service delivery mechanisms if we test all patients¹⁹.

Furthermore, the ethics of universal genetic testing must be considered. Will billing insurance for 100 patients to undergo germline testing have a cost-benefit in preventing future cancers in two people with hereditary cancer risk? What is the threshold at which resource allocation is equitable and universal germline testing can help address disparities in cancer care? If germline testing is opt-out, how can we ensure appropriate education so that patients don’t receive information they are not interested in? And importantly, in communities where genetic research has previously been harmful, how do we rebuild trust to equitable access? As the oncology and genetics communities approach the inevitable shift of broader germline genetic testing in cancer patients, many questions are left to be answered. Inter-disciplinary collaborations across multiple stakeholders will be required to create a smooth transition to this next stage in precision and preventive oncology.

References

1.        Collins FS, Morgan M, Patrinos A. The Human Genome Project: lessons from large-scale biology. Science. 2003;300(5617):286-290.

2.        Miki Y, Swensen J, Shattuck-Eidens D, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266(5182):66-71.

3.        Wooster R, Bignell G, Lancaster J, et al. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995;378(6559):789-792.

4.        Risch HA, McLaughlin JR, Cole DE, et al. Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. J. Natl. Cancer Inst. 2006;98(23):1694-1706.

5.        Goodwin S, McPherson JD, McCombie WR. Coming of age: ten years of next-generation sequencing technologies. Nature reviews. Genetics. 2016;17(6):333-351.

6.        Costello V. The Impact of Association for Molecular Pathology v. Myriad Genetics on Cancer Genetic Counseling Practice [M.S.]. Ann Arbor, Sarah Lawrence College; 2014.

7.        Daly MB, Pilarski R, Berry M, et al. NCCN Guidelines (R) Insights Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 2.2017 Featured Updates to the NCCN Guidelines. J. Natl. Compr. Canc. Netw. 2017;15(1):9-19.

8.        Daly MB. Prostate cancer genetic testing: NCCN familial high-risk assessment: breast/ovarian. The Canadian journal of urology. 2019;26(5 Suppl 2):29-30.

9.        Daly MB, Pilarski R, Yurgelun MB, et al. NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 1.2020. J. Natl. Compr. Canc. Netw. 2020;18(4):380-391.

10.      Alegre N, Perre PV, Bignon YJ, et al. Psychosocial and clinical factors of probands impacting intrafamilial disclosure and uptake of genetic testing among families with BRCA1/2 or MMR gene mutations. Psychooncology. 2019;28(8):1679-1686.

11.      McLeavy L, Rahman B, Kristeleit R, et al. Mainstreamed genetic testing in ovarian cancer: patient experience of the testing process. Int. J. Gynecol. Cancer. 2020;30(2):221-226.

12.      Nicolosi P, Ledet E, Yang S, et al. Prevalence of Germline Variants in Prostate Cancer and Implications for Current Genetic Testing Guidelines. JAMA oncology. 2019.

13.      Beitsch PD, Whitworth PW, Hughes K, et al. 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. 2019;37(6):453-460.

14.      Shindo K, Yu J, Suenaga M, et al. Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma. J. Clin. Oncol. 2017;35(30):3382-3390.

15.      Samadder NJ, Riegert-Johnson D, Boardman L, et al. Comparison of Universal Genetic Testing vs Guideline-Directed Targeted Testing for Patients With Hereditary Cancer Syndrome. JAMA oncology. 2021;7(2):230-237.

16.      Catenacci DV, Amico AL, Nielsen SM, et al. Tumor genome analysis includes germline genome: are we ready for surprises? Int. J. Cancer. 2015;136(7):1559-1567.

17.      Robson ME, Bradbury AR, Arun B, et al. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J. Clin. Oncol. 2015;33(31):3660-3667.

18.      Hoskovec JM, Bennett RL, Carey ME, et al. Projecting the Supply and Demand for Certified Genetic Counselors: a Workforce Study. J Genet Couns. 2018;27(1):16-20.

19.      Stoll K, Kubendran S, Cohen SA. The past, present and future of service delivery in genetic counseling: Keeping up in the era of precision medicine. Am. J. Med. Genet. C Semin. Med. Genet. 2018;178(1):24-37.