Removing Restrictions to Germline Testing

Genomic advances brought about by developments in laboratory and computational technologies have resulted in several major breakthroughs across medical disciplines over the past decade.¹ Oncology in particular has been a major benefactor, with the characterization of cancers’ DNA, gene expression, proteins, and many other molecular features yielding an increased understanding of cancer biology, the holistic tumor ecosystem, and novel diagnostic and therapeutic strategies.² However, even amidst this progress, the global cancer burden is growing³—in the US, incidence rates of many common cancers are increasing while the age of onset is falling.⁴ In light of this, many have focused on genomics’ potential in cancer diagnosis, with some considering universal germline genomic testing the key to winning the war against cancer.⁵ But is it a feasible and effective approach—and, if so, what part does the clinical lab play?

Restricted by guidelines

There are two primary ways in which genetic testing for inherited cancer risk can improve outcomes for both patients and their families. The first is increasing the survival of diagnosed patients through precision therapies based on the sequencing of inherited DNA—such as the recently published activation of select patients’ natural killer cells by a targeted cancer “vaccine” based on the XPO1 protein.⁶ The second is the personalization of cancer screenings and preventive therapies for relatives of cancer patients who may be at increased risk.⁷

Historical clinical guidelines put forward by professional societies only recommend germline genomic testing in limited circumstances, specifically for the patients at highest risk of carrying pathogenic or likely pathogenic germline variants (PGVs) of a few select genes.⁸ The reasons: germline genomic testing was costly, PGVs were perceived as rare in the general population and—at the time—lacking in clinical utility. These guidelines also served as the basis for medical coverage policies’ determination of patients’ eligibility and the genes included in testing. Although patient eligibility between payers overlaps, coverage differences can make it difficult for clinicians to determine their patients’ eligibility, further limiting the number who receive such testing.

Opening the barriers

One of the main arguments in favor of a universal germline genomic testing approach is that current testing criteria fail to identify substantial numbers of patients with PGVs. According to a pan-cancer study, more than half of patients with actionable PGVs don’t receive genomic germline testing under legacy guidelines.⁹ This finding supports other studies exploring the issue in individual cancers.⁸

However, simply being eligible for germline testing doesn’t mean that patients will receive it. A recent study showed that many women diagnosed with early-stage breast cancer don’t receive genetic counseling and testing into survivorship¹⁰—even if they have an indication on the basis of clinical guidelines at the time of diagnosis or follow-up. “Targeted guidelines are just too complicated, and the genetic risk assessments cannot happen efficiently after diagnosis—planning and treatment management following breast cancer diagnosis necessarily evolves quickly,” explains lead author Steven Katz, a professor of health management and policy at the University of Michigan. “Too many patients who carry a clinically meaningful pathogenic variant fall through the cracks, although there’s little evidence that variants of unknown significance results foment overtreatment or patient worry.”

The results Katz and his team observed remained constant between racial and ethnic groups, highlighting the progress made in closing inequality gaps—but this ubiquity also indicates that universally widening access may be the key to further progress in increasing testing prevalence. “Reassuringly, we didn’t observe significant differences in patient reports of genetic testing or counseling across race and ethnic groups,” Katz explains. “That’s good news, and many recent articles show high-quality breast cancer care across potentially vulnerable groups like minoritized groups or those with lower education. We’re closing these gaps, at least in breast cancer management—so the barriers are universal. Our article demonstrates that it’s important to consider genetic testing into survivorship but, because results can influence initial therapy, it’s best for testing to occur early during the treatment planning period. I support universal genetic risk assessment with the option for germline genetic testing after diagnosis of breast cancer.”

Change is coming

Germline genomic testing approaches are beginning to change—the result of a growing body of evidence. Following the publication of studies demonstrating the utility of universal germline genetic testing for pancreatic and ovarian cancers,^11,12 the National Comprehensive Cancer Network (NCCN) updated their guidelines in 2021 to recommend testing all patients with these types of cancer for several years.¹³ Similar changes have been made by professional societies (such as the American Society of Breast Surgeons’ recommendation of genetic testing for all breast cancer patients),¹⁴ health insurers (including Medicare’s expanded coverage of germline multigene panel testing),¹⁵ and healthcare systems such as Mayo Clinic.¹⁶

However, altering testing guidelines doesn’t automatically raise testing levels. One of Katz’s other studies highlighted that only 6.8 percent of patients underwent germline genetic testing after a cancer diagnosis, even under the updated NCCN practice guidelines.¹⁷ “As we noted in our study, although there are many possible explanations for this (including individual preferences and insurance coverage), strategies—such as education of clinicians, incorporating genetic counselors into oncology practices, telemedicine, and electronic health record reminders—warrant study to address the gaps in testing,” he says. However, Katz and his team did note that, even though germline testing levels never reached practice guidelines, it did substantially increase over time. This indicates that the growing evidence regarding the benefits of this testing and the treatment options it affords may be shifting the tide.

As germline testing’s scope widens, Katz believes that there are multiple roles the clinical lab can play in increasing the testing rate. First, labs should promptly process and report the results of germline testing orders along with appropriate quality assurance measures. Second, their clinical genomic testing reports should provide clear, easily understood results and highlight essential information to reduce the potential for misinterpretation.¹⁸ Finally, laboratorians should stay aware of advancements in genomic germline testing and work with health systems to incorporate updates alongside other cancer prevention and control strategies.

“Genetic testing after diagnosis of cancer is growing—and there are implications of germline testing for families with hereditary cancer syndromes,” he says. “It’s not about the test itself, but about patient-centered quality of decision-making and treatment management after diagnosis and strong continuity of care into survivorship. Laboratories and clinicians must work closely with one another to ensure the highest-quality information is available to help make those decisions.”

References:

1. C Auffray et al. Ten years of Genome Medicine. Genome Med. 2019;11(1):7. doi:10.1186/s13073-019-0618-x.
2. D Wang et al. Accelerating the understanding of cancer biology through the lens of genomics. Cell. 2023;186(8):1755–1771. doi:10.1016/j.cell.2023.02.015.
3. World Health Organization. Global cancer burden growing, amidst mounting need for services. February 1, 2024. Available at: https://www.who.int/news/item/01-02-2024-global-cancer-burden-growing–amidst-mounting-need-for-services.
4. RL Siegel et al. Cancer statistics, 2024. CA Cancer J Clin. 2024;74(1):12–49. doi:10.3322/caac.21820.
5. V Subbiah, R Kurzrock. Universal germline and tumor genomic testing needed to win the war against cancer: genomics is the diagnosis. J Clin Oncol. 2024;41(17):3100–3103. doi:10.1200/JCO.22.02833.
6. MD Blunt et al. The nuclear export protein XPO1 provides a peptide ligand for natural killer cells. Sci Adv. 2024;10(34):eado6566. doi:10.1126/sciadv.ado6566.
7. N Tung et al. Selection of germline genetic testing panels in patients with cancer: ASCO guideline. J Clin Oncol. 2024;42(21):2599–2615. doi:10.1200/JCO.24.00662.
8. ED Esplin et al. Universal germline genetic testing for hereditary cancer syndromes in patients with solid tumor cancer. JCO Precis Oncol. 2022;6(1):e2100516.
9. D Mandeiker et al. Mutation detection in patients with advanced cancer by universal sequencing of cancer-related genes in tumor and normal DNA vs guideline-based germline testing. JAMA. 2017;318(9):825–835. doi:10.1001/jama.2017.11137.
10. SJ Katz et al. Genetic counseling, testing, and family communication into survivorship after diagnosis of breast cancer. J Clin Oncol. 2024; online ahead of print. doi:10.1200/JCO.24.00122.
11. MB Daly et al. Genetic/familial high-risk assessment: breast ovarian and pancreatic, version 2.2021, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2021;19(1):77–102. doi:10.6004/jnccn.2021.0001.
12. C Hue et al. Multigene hereditary cancer panels reveal high-risk pancreatic cancer susceptibility genes. JCO Precis Oncol. 2018;2:PO.17.00291. doi:10.1200/PO/17.00291.
13. JL Stafford et al. Reanalysis of BRCA1/2 negative high risk ovarian cancer patients reveals novel germline risk loci and insights into missing heritability. PLoS One. 2017;12(6):e0178450. doi:10.1371/journal.pone.0178450.
14. ER Manahan et al. Consensus guidelines on genetic`testing for hereditary breast cancer from the American Society of Breast Surgeons. Ann Surg Oncol. 2019;26(1):3025–3031. doi:10.1245/s10434-019-07549-8.
15. Medicare Coverage Database. Next Generation Sequencing (NGS). January 27, 2020. Available at: https://www.cms.gov/medicare-coverage-database/view/ncd.aspx?NCDId=372.
16. Mayo Clinic. Broad-based testing increases detection of inherited germline variants in patients with cancer. December 18, 2020. Available at: https://www.mayoclinic.org/medical-professionals/cancer/news/broad-based-testing-increases-detection-of-inherited-germline-variants-in-patients-with-cancer/mac-20505441.
17. AW Kurian et al. Germline genetic testing after cancer diagnosis. JAMA. 2023;330(1):43–51. doi:10.1001/jama.2023.9526.
18. ZC Deans et al. Recommendations for reporting results of diagnostic genomic testing. Eur J Hum Genet. 2022;30(9)1011–1016. doi:10.1038/s41431-022-01091-0.