New Evidence Addresses Preferences for, Implications of Returning Sequencing Results

Clinical uses for comprehensive sequencing, including whole exome sequencing (WES) and whole genome sequencing (WGS) are increasing. Although some recommendations exist for the reporting of secondary findings in comprehensive sequencing, this topic remains controversial.

Concerns include psychosocial risks for patients who derive minimal or no clinical benefit from the results, as well as the implications for family members and children. Several research groups are now beginning to provide answers regarding patient preferences, as well as psychosocial and behavioral consequences of return results in large samples of patients. Recent studies show preferences for results among patients with advanced cancer, the potential benefit of returning actionable secondary results along with information on hereditary predisposition for a nonactionable condition, and the use of results among adoptees, without the context of family history.

Findings in Advanced Cancer Patients
The majority of patients with advanced cancer want both cancer-related and incidental findings from whole exome sequencing (WES), according to a study published online Feb. 11 in Genetics in Medicine. Patients' low levels of genetic knowledge and oncologists' inexperience with large-scale sequencing present challenges to implementing paired germline and somatic sequencing in practice, the authors say.

Recent studies point to the increased power of sequencing results to unequivocally distinguish cancer-related genomic alterations when both somatic and germline DNA are sequenced in parallel. However, paired sequencing can also uncover previously unsuspected inherited cancer risk, which hold implications both for patient treatment, as well as their families.

The Dana-Farber Cancer Institute's CanSeq study, launched in February 2013, evaluates the integration of paired WES in clinical care. The researchers conducted surveys and interviews to understand 27 oncologists' attitudes about WES and to identify 167, stage IV lung and colorectal cancer patients' preferences for learning WES findings.

The CanSeq researchers found that although oncologists have extensive experience ordering somatic tests (median, 100 per year), they have less experience with germline tests (median, two germline cancer predisposition tests per year). Gastrointestinal oncologists ordered or interpreted more germline tests during the prior year than thoracic oncologists, reflecting recommendations for testing for the inherited Lynch Syndrome.

Oncologists intended to disclose most WES results (both somatic and germline). Many oncologists noted that the actionability of the germline results would be a key determinant of disclosure, as they would be less willing to disclose results if it did not have implications for cancer therapy or prevention. Oncologists were also less confident in their abilities to provide psychosocial support related to negative prognostic results and cancer risk testing.

"Our findings advance the field by demonstrating that although physicians anticipate many challenges to delivering care involving large-scale sequencing, patients with incurable cancer express a strong desire to learn about genomic findings whether or not they have relevance to their immediate medical care," write the authors led by Stacy Gray, M.D. "Given the complexity of the results and the familial implications of germ-line findings, institutions that offer WES or whole genome sequencing may need to make relevant clinical and counseling expertise available to oncologists, patients, and patients' family members."

Patients had moderately low levels of genetic knowledge (mean 4 correct out of 7). Almost all patients (more than 95 percent) chose to learn most cancer-related, pharmacogenetic, and carrier status findings, but fewer chose to receive negative prognostic results (84 percent) and results suggesting predisposition to untreatable noncancer conditions (85 percent).

Findings for Dual-Risk Conditions
Disclosure of pleiotropic information may actually decrease distress among persons at increased genetic risk for two conditions, according to a study published Feb. 2 in the Annals of Internal Medicine. Pleiotropic genes pose a challenge to communicating genetic test results because the variant may unexpectedly confer knowledge of a separate disease risk. The ε4 allele of the apolipoprotein E (APOE) gene, which is common in the general populations and robustly associated with risk for Alzheimer disease (AD), has a weaker and less well-known association with risk for coronary artery disease (CAD).

Researchers from the Risk Evaluation and Education for Alzheimer disease (REVEAL) Study Group randomly assigned 257 participants seeking a genetic risk assessment for AD to receive risk information on AD only (AD-only) or on AD and CAD (AD+CAD). More than two-thirds of enrollees (69 percent) had an AD-affected first-degree relative. Outcomes were measured at six weeks, six months and 12 months following testing. Genetic counselors provided pre-test counseling.

The REVEAL researchers found that anxiety and depression were similar between participants receiving AD-only information and those also receiving secondary information on CAD risk. APOE ε4 carriers, those participants at increased risk for disease, experienced less test-related distress at 12 months if they also received CAD information. Participants in the AD+CAD groups also reported more health behavior changes, regardless of APOE genotype.

Unique Case of Adoptees
Adoptees use direct-to-consumer personal genomic testing (PGT) to gain an understanding of their genetic identities and to fill in "inaccessible information" about their family history, according to a study published online Jan. 28 in Genetics in Medicine. The evidence also shows that adoptees use information gleaned from PGT in a manner similar to nonadoptees.

Adoptees face a catch-22. PGT provides an easy means of obtaining personalized information regarding disease risks, inherited traits, pharmacogenomics, and ancestry. Yet, critics say giving results without the context of family history, and/or clinician interpretation, may lead to false reassurance or unnecessary alarm by results. There is currently no consensus recommendation on the appropriateness of disclosing genetic results to patients with limited family history data.

The Impact of Personal Genomics (PGen) Study surveyed new 23andMe (Mountain View, Calif.) and Pathway Genomics (San Diego) customers before and 6 months after receiving PGT results (initial recruitment from March to July 2012). Adoptees' and nonadoptees' PGT attitudes, expectations, and experiences were compared.

The PGen Study Group found that five percent of the 1,607 participants were adopted. Adoptees were ten times more likely to cite limited knowledge of family health history and 2.7 times more likely to cite the opportunity to learn genetic disease risks as strong motivations for PGT, compared to nonadoptees. In terms of PGT-motivated health-care utilization or health-behavior change, there were no significant differences between adoptees and nonadoptees. PGT results caused 41 percent of all participants to utilize a health-care service and 56 percent to change a health behavior (diet, exercise, medications, or supplements) within 6 months of receiving PGT results.

"Our results may help health care professionals and policy makers to better understand the desires of adopted patients and how the provision of genetic information may affect their health," writes senior author Robert Green, M.D., from Brigham and Women's Hospital in Boston. "It remains to be seen whether genetic-risk predictions from PGT can be useful in the absence of family history information."

Takeaway: Emerging studies are beginning to fill in uncertainty regarding the return of secondary sequencing findings among different patient populations. These findings could inform future best practices.