Germline Testing Outside the Guidelines: Can it Address Health Disparities?

Targeted Therapies in OncologyJune 2023
Volume 12
Issue 8
Pages: 16

The completion of the Human Genome project has ushered in a new era in our understanding of cancer.

The completion of the Human Genome project has ushered in a new era in our understanding of cancer. We now recognize cancer as a complex set of diseases with multistep events and understand the vast possibilities of genetically targeted treatment options as well as the way in which existing genetic variations can lead to a high risk for disease. The rapid strides have allowed us to understand the complex interaction of inherited genetics, epigenetics, environmental factors, and social determinants of health (SDoH).2 These developments hold the promise of revolutionizing cancer prevention and treatment by combining genotypic, phenotypic, and social factors.3

Broad-based germline genetic testing for patients with various cancers can identify mutations that may warrant a change of treatment. Further, results may identify individuals at a higher risk of carrying germline mutation and actionability.4,5

Generally, germline genetic testing has focused more on early-stage cancers with the idea of helping patients who would benefit from preventive risk reduction measures such as chemoprevention, risk reduction surgery, and enhanced cancer surveillance, and identifying family members at risk. This is especially the case with the FDA’s approval of the first PARP inhibitor for patients with advanced ovarian cancer whose tumor harbors germline BRCA1/2 alterations.6,7

Germline genetic variants that affect cancer risk, prevention, and treatment strategies are implicated in up to 20% of cancers. Only a fraction of people at risk for hereditary cancer syndromes undergo diagnostic genetic testing. Barriers to testing at the patient, payer, systemic, and provider levels, include gaps in knowledge and poor access to specialty genetics services.

Universal genetic testing of a pan- cancer patient population revealed that 15% of patients (n = 44/284) carried a pathogenic germline variant (PGV) in a cancer susceptibility gene, and that over half (n = 23/44) of those with PGVs failed to meet current guidelines for clinical genetic testing.8-10 The clinical actionability associated with expanded panel testing has demonstrated its potential to alter patient care.


Needs assessment for broader access Despite the minimizing of barriers to genetic testing, non-White patients are less likely to receive recommended cancer genetics follow-up than White patients. If patients are not adequately genotyped, they may miss opportunities to participate in precision medicine or clinical trials and/or to elect risk-reducing strategies to prevent a second malignancy.


We performed germline testing, outside of guidelines, as part of a real-world evidence registry to identify the prevalence of inheritable mutations within an ethnically diverse patient population in rural and suburban South Carolina. We undertook the testing in an effort to address CHDs in patients presenting at earlier age or with rare tumors or recurrent/ multiple malignancies.

An institutional review board (IRB)- approved, single-center prospective registry was initiated with a single community clinic at Carolina Blood and Cancer Care Associates (CBCCA). Eligibility criteria included patients unselected for personal or family history, stage, or histology who had not been previously tested. Patients aged 18 to 90 years consented to be tested and underwent an 84-gene germline panel test. Electronic case report forms that were compliant with the Health Insurance and Portability and Accountability Act were distributed to clinicians and used to collect information on patient diagnoses, National Comprehensive Cancer Network testing criteria, and results-based recommendations.

Two separate studies were carried out, with the first one conducted using the Sema4 test and the second conducted using the Invitae test.


We identified 265 individuals outside the guidelines concordance. Sixty-three percent were male. Patients reported their race as African American (n = 71), White (n = 182), or Asian American (n = 12).

Rare germline findings included Li-Fraumeni syndrome, Fanconi syndrome, Perlman syndrome, and von Hippel-Lindau disease. Our findings are summarized in the FIGURE.


Inherited cancer predisposition was believed to be rare because a very small number of patients undergo germline testing. The majority of data on inheritable mutations are limited to patients of Northern European ancestry, and hence our knowledge and awareness, as well as our ability to identify whether a mutation is truly deleterious or a variant of uncertain significance, is quite limited due to lack of representation of ethnic minorities in such studies. Multiple publications have identified and emphasized the need for much broader access to germline testing outside of existing guidelines.

There is large phenotypic variability in the expression of inherited cancer syndrome. This variability can be explained by factors such as allelic heterogeneity, environmental effects, or the presence of mutations on 2 or more inherited cancer genes in the same individual (ie, multilocus inherited neoplasia allele syndrome, or MINAS).

Although the literature reports that inherited mutations are thought to play a role in approximately 5% to 10% of all cancers. Recent data, including those of the Intercept Somatic (IRB 18-00326) study,10 have shown the prevalence of pathogenic variants in germline mutations to be as high as 28% in certain cancers. Combining the data from these reports in the literature and additional factors such as environmental influences (including the impact of SDoH) can lead to the detection of more than 50 hereditary cancer syndromes with different phenotypic expressions. The standard clinical practice for guidelines in concordant testing has its own limitations. After detecting a mutation in a specific gene, the clinician may attribute any tumors that are not typical of the detected syndrome to phenotypic variability. Thus, the patient may receive suboptimal treatment and any risks to relatives might be incorrectly estimated or go undetected.

Studying patients with multiple mutations could provide insights into how the functions of the relevant genes may be related and result in an enhanced or novel phenotype. Findings from multiple studies8,9 have validated the role of germline testing and actionable interventions; however, the uptake of universal germline testing remains low across all sectors.

Factors That Limit Germline Testing

Shortage of Genetic Counselors

There is a shortage of genetic counselors, especially in underserved rural communities. We therefore feel that an oncologist well trained in interpretation and management of germline testing implications may be appropriate to ensure that CHDs do not worsen due to lack of access to germline testing.

Payer-Related Factors

Limited coverage and health policy are frequently a hindrance for access to testing. In findings from a study published in JCO Precision Oncology, Hsiao et al11 report that limited coverage and low reimbursement for next-generation sequencing (NGS) testing are barriers to implementation. Broader reimbursement policies are needed to adopt pan-cancer NGS testing into clinical practice.

Physician and Health Care Team Education

The rapid development of NGS technology and molecular profiling in oncology has not been matched with appropriate provider education. Physicians also continue to struggle to manage the large amounts of data with unclear therapeutic significance.

Social Determinants of Health

Ethnically diverse populations suffer from a lack of access to adequate cancer diagnosis and treatment. There is a need to study the impact of SDoH and address them appropriately. Failure to address these will lead to drug development processes lacking demographic diversity in clinical trials. This can further contribute to disparities in care and health outcomes in ethnically diverse populations.

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10. Samadder NJ, Riegert-Johnson D, Boardman L, et al. Comparison ofuniversal genetic testing vs guideline-directed targeted testing for patients with hereditary cancer syndrome. JAMA Oncol. 2021;7(2):230-237. doi:10.1001/jamaoncol.2020.6252
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