Published online Aug 24, 2024. doi: 10.5306/wjco.v15.i8.975
Revised: July 15, 2024
Accepted: July 23, 2024
Published online: August 24, 2024
Processing time: 141 Days and 6 Hours
Recent advancements in next generation sequencing have allowed for genetic information become more readily available in the clinical setting for those affected by cancer and by treating clinicians. Given the lack of access to geneticists, me
Core Tip: Mainstreaming has allowed for improved and readily available access to next generation sequencing testing in some regions of the world by allowing oncologists to order genetic testing. Pitfalls encountered with mainstreaming include adequate patient counseling on unanticipated genetic results as well as follow-up of variants of unknown significance (VUS) which have implications for tested individuals and family members. Genetic registries following VUS may provide a formal avenue for patients to receive adequate follow-up and counseling if VUS are later identified as malignant. A “layered consent model” as well as system of categorizing genes of interest may help in preserving patient autonomy and upholding the medical ethical tenets of justice and non-maleficence.
- Citation: Kumar P, Benjamin DJ, Darabi S, Kloecker G, Rezazadeh Kalebasty A. Implications of genetic testing and informed consent before and after genetic testing in individuals with cancer. World J Clin Oncol 2024; 15(8): 975-981
- URL: https://www.wjgnet.com/2218-4333/full/v15/i8/975.htm
- DOI: https://dx.doi.org/10.5306/wjco.v15.i8.975
With advances in sequencing technologies over the past decade, next generation sequencing (NGS) has become more readily available and integrated into daily clinical practice. In the past, techniques such as polymerase chain reaction and Sanger DNA sequencing were utilized to sequence DNA. However, since the 2000s, several NGS sequencers have become commercially available utilizing technologies such as short- and long-read sequencing[1]. NGS is employed to detect hereditary cancer mutations, somatic mutations, and genomic rearrangements that allow clinicians to practice precision medicine by matching the right treatment with the right individual. For example, identifying a germline breast cancer susceptibility gene 1 (BRCA 1) or breast cancer susceptibility gene 2 (BRCA 2) mutation not only identifies an individual at increased risk of several cancers but also has potential therapeutic implications for individuals diagnosed with prostate, ovarian or breast cancer[2-4].
As oncologists increasingly employ more genetic and genomic testing, the practice of mainstreaming has also increased. “Mainstreaming” refers to the direct ordering of these tests by clinicians without the involvement of geneticists or genetic counselors[5]. As a result, clinicians shoulder responsibilities traditionally carried by genetic counselors, including the complex process of consenting and counseling patients. One aim of mainstreaming is to facilitate faster decision-making regarding treatment options in patients with advanced diseases[6,7]. Due to a shortage of genetic cou
Several studies have identified benefits of mainstreaming. For example, a systematic review of genetic assessment in women with ovarian cancer found that mainstreaming was the most successful strategy in improving rates of genetic testing[14]. In addition, a study in the United Kingdom demonstrated that mainstream genetic testing could provide cost-effective and patient-centered testing for breast cancer susceptibility gene mutations utilizing cancer-based criteria[12]. Moreover, a systematic review of mainstreaming revealed that mainstream genetic testing appears feasible without any significant barriers[15]. However, the review did identify potential pitfalls associated with mainstreaming. For example, a Norwegian study found that 23% of women with breast cancer who did not meet Norwegian Breast Cancer Group (NBCG) criteria were offered genetic testing by an oncologist or surgeon[16]. Conversely, only 75% of women who did fulfill NBCG criteria were offered genetic testing. The study highlighted a potential lack of clinician knowledge on patient eligibility for genetic testing. However, several challenges with mainstream genetic testing remain including misinterpretation of genetic test results and consequently incorrect management such as inappropriate screening or prophylactic interventions. In addition, clinicians without adequate background in genetics may not order the correct genetic test based off evaluation of a patient’s presentation and history, leading to possible missed diagnoses[17].
Advances in sequencing technologies have also increased the ease of testing and the abundance of genetic information available. NGS provides whole-exome sequencing and multigene testing panels as opposed to traditional panels with select genes tested. NGS utilizes tumor tissue samples or patient blood samples, known as a “liquid biopsy”[18-21].
Several disadvantages of NGS include wait times up to several weeks, increased cost of testing as compared to single-gene tests, and difficult to interpret and/or unexpected results with testing[22]. For instance, NGS may find mutations in genes of interest plus “secondary” or “incidental” findings in somatic testing. These results include germline pathogenic/likely pathogenic findings, variants of unknown significance (VUS), or unsolicited discoveries relevant to other diseases than cancer (secondary findings)[5]. These unanticipated findings may challenge clinicians who may be unable to interpret these results and thus cannot properly inform patients, creating an ethical dilemma in the consent process.
Germline genetic pathogenic/likely pathogenic variants may have various negative health implications, including an increased risk of other cancers, increased risk of cancer recurrence, and increased risk of cancer heritability. The discovery of germline variants may therefore alarm patients, especially regarding the possible need for additional “cascade” or familial testing[5]. However, cascade testing could be beneficial to patients’ families if adequately counseled.
On the other hand, VUS are defined as variants that may not be associated with disease and do not meet the criteria for interpretation of either benign or pathogenic classification[23-25]. The ambiguity of VUS results may nonetheless cause additional stress for the individual undergoing testing[23,26]. In fact, a study of 209 women who received uninformative BRCA 1 or BRCA 2 results experienced psychological distress lasting up to one year after testing[27]. A separate study evaluating gene panel testing for hereditary breast and ovarian cancer similarly found emotional distress in individuals with a VUS result[23]. Moreover, qualitative studies have revealed that patients experience a range of psychological responses to VUS including disappointment, sadness, shock and regret for testing due to the VUS result[28]. The American College of Medical Genetics recommends that VUS results not be used to alter clinical care as these results may confuse and worry patients who do not understand the implications of these results. This, in turn, places burden on clinicians on how to report these results to individuals in the clinical setting[24,29,30].
To date, there is a lack of standardization on reporting or managing VUS findings[24,31-34]. The lack of guidance increases clinicians’ discomfort with counseling patients, as they may not know how to explain all findings. Moreover, time constraints in the clinical setting present another challenge when disclosing unexpected results within a mainst
Current guidelines from oncology societies help clinicians decide which patients should receive germline testing and how these findings may be reported. The National Comprehensive Cancer Network (NCCN) guidelines state that germline testing is clinically indicated not only in patients with a strong family history of cancers but also in individuals with breast cancer (with certain age demographics, with specific features or male breast cancer), pancreatic cancer, metastatic prostate cancer, or in those with epithelial ovarian cancer[36]. The recommendation for germline testing in these cases may be to inform patient reproductive decisions, prophylactic risk-reduction surgeries or to identify therapeutic options in treating cancer[36].
Given the prevalence of NGS testing, reporting of secondary germline results in cancer patients without first-line indications is increasingly common. The American Society of Clinical Oncology (ASCO) issued guidelines in 2014 specifically to address challenges associated with NGS. According to ASCO, clinicians should educate patients on the possibility of incidental findings and their associated risks, including germline findings. In addition, ASCO recommends patients should be given adequate pre-test counseling to decide whether to receive germline (or other incidental) results. Clinicians should refer patients to genetic counselors in cases where patients have difficulty deciding. The guidelines also specify that laboratories are responsible for ensuring reporting of clinically relevant germline findings to interested patients. On the other hand, for patients who opt out of germline findings, laboratories should develop methods to report only somatic findings[37].
ASCO also encourages counseling patients on the possibility of receiving VUS results. Education on receipt of VUS results should adequately explain the difference between high penetrance and well-studied genes versus moderate penetrance and less studied genes[37]. However, the society acknowledges that there is little guidance on which genes should be included for testing in different panels, the clinical significance of VUS results, and how best to counsel patients on receipt of VUS[21,37-40]. ASCO, therefore, concludes that only experts should be involved in ordering and inter
Genomic registries |
Evidence-based network for the interpretation of germline mutant alleles |
International society for gastrointestinal hereditary tumours |
Clinical genome resource (clingen) |
Clinical cancer genomics community research network of the United States, Mexico, and South America |
Prospective registry of multiplex testing |
Clinvar |
Despite increased utilization of genetic and genomic testing, multiple practical barriers remain regarding the accessibility of testing, counseling and subsequent management of test results. While mainstreaming represents one solution to increase access to genetic counseling, patients who struggle to fully understand the implications of testing may still benefit from referral to genetic counselors for additional information. However, owing to the significant shortage of geneticists and genetic counselors and the disproportionate growth of testing, patients’ wait time for counseling can be several months[41,42]. Patients may also find genetic testing and counseling to be cost prohibitive due to variability among insurance providers. Under the Affordable Care Act, coverage of genetic counseling and testing in many cancers is not required, thus leaving coverage of these services up to each health plan’s discretion[37].
Further management of genetic testing findings, especially for VUS results, is also challenging given that VUS findings may eventually be reclassified. Communicating these changes to a patient or family, especially if a patient has already died, may be problematic without proper initial consent. Moreover, there is a significant delay in the development of recommendations and guidelines for cancer screening for new variant classifications which further adds to the down
Standardizing the consent process for genetic testing and mainstreaming can reduce both the practical barriers and ethical challenges of genetic and genomic testing. The consent process should include all the details about the risks and benefits of testing and possible secondary findings. Patients should be able to opt out of select secondary findings they wish not to know about. To obtain informed consent, the patients should be provided pre-test counseling either by a certified genetic counselor or professionally developed pre-counseling video education. All patients should also receive post-test coun
Standardization of the consent process for testing may address the underlying ethical challenge of the potential gaps in patient knowledge associated with genetic and genomic testing. Gaps in patient knowledge may result from clinician discomfort with the consent process in mainstreaming models or uncertainties in clinical significance and reporting of secondary germline and VUS findings.
Some models have consequently been proposed to help guide informed consent in testing. For instance, Fecteau et al[32] suggested grouping genes within multigene panels into three broad categories based on the level of cancer risk plus the availability of management guidelines to help educate patients about various results. These panels include Category 1, Category 2, and Category 3 genes. Genes classified as Category 1 include genes that are associated with a high risk of cancer and have well-studied management guidelines. Category 2 genes are those that are associated with moderate risk of cancer but do not have well-established guidelines for management. Lastly, Category 3 genes may be prevalent in some cancer populations, but their association with cancer risks are not fully known; as such, these genetic aberrations have no corresponding established management guidelines[32]. For individuals undergoing genetic testing who may be uncomfortable with the possibility of test results with vague guidelines for management, such a category system of gene testing may provide greater patient autonomy and uphold non-maleficence by avoiding unnecessary stress and harm associated with unclear test results to tested individuals.
Alternatively, Bunnik et al[5] recommend a “layered consent” model, which entails key information, or “the first layer,” is given to all patients with more detailed information given on patient request. This model recognizes that patients may have different informational needs that allow them to make an informed decision. Importantly, however, the authors note that there is no consensus about what elements of consent are considered “key” in genetic testing[5,23,43]. They argue that the possibility of germline variants, VUS, and unsolicited findings should all be disclosed as part of the “first layer” of consent[5]. An advantage of the “layered consent” model is adhering to the ethical pillar of justice by treating all individuals equally by providing key information to all tested individuals while also supporting patient autonomy by allowing individuals to either obtain or refrain from access to more information.
In conclusion, although NGS and the process of mainstreaming have expanded the capabilities and accessibility of genetic and genomic testing, ethical dilemmas surrounding informed consent prior to testing have also arisen. Informed consent may be complicated by unexpected results involving germline pathogenic/likely pathogenic variants or VUS, which may be challenging to explain to individuals undergoing testing and may not have clear management. Patient comprehension and clinician comfort with informed consent for these tests may be enhanced by standardizing the consent process. In addition, a categorization of genetic testing or layered consent model may help mitigate ethical dilemmas in the testing process while upholding the pillars of medicine such as autonomy, non-maleficence, and justice. Given the increased utilization of NGS in the era of precision oncology, further discussion and standardization of testing and reporting of results is warranted.
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