July 25, 2019
9 min read

DTCandWe: Oncology providers must understand direct-to-consumer testing’s limitations, implications

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Donna was a young mother of two whose mom and maternal aunt died of breast cancer at early ages.

Concerned for her daughter, Donna wondered whether she may be genetically at risk for breast cancer.

She explored testing options and settled on purchasing a direct-to-consumer (DTC) test from a local retailer, which required a simple collection of saliva and shipment of the sample.

Jill S. Bates, PharmD, MS, BCOP, FASHP
Jill S. Bates

Increasing demand for health information among consumers like Donna — along with the declining cost of genotyping — have fueled an explosion in DTC testing. The global market is projected to exceed $6 billion by 2028, up from an estimated $684 million in 2017, according to a report issued in May by the market intelligence firm BIS Research.

DTC testing provides consumer access to an in vitro diagnostic, without the involvement of a health care provider. Alternatively, some vendors employ physicians who order the test upon consumer request and interpret the results, thus functioning in a similar way to a DTC testing model.

This has significant implications for the oncology community, as FDA-approved tests provide information about genetic risk for cancer and soon will yield insights into drug disposition.

Empowering the consumer

DTC tests — introduced with the goal of empowering consumers to take charge of their health — are categorized as medical devices by the FDA.

To date, one company — 23andMe — has received FDA approval for DTC testing.

FDA regulatory review of DTC testing includes evaluation of:

  • the test’s analytical validity, meaning whether it reliably and accurately measures what it claims to measure;
  • its clinical validity, meaning whether the measurement is predictive of a certain state of health; and
  • the claims a company makes about the test and how well it works.

FDA does not evaluate a test’s clinical utility.

Although DTC devices are classified as in vitro diagnostics, they are not technically diagnostic.

It is important to remind consumers that only a College of American Pathologists (CAP)- and Clinical Laboratory Improvement Amendments (CLIA)-certified lab should provide DTC testing results. Not all DTC vendors have these certifications, which are important to confirm that a test meets specific quality standards related to accuracy and reliability of results.

Donna was relieved when her genetic results returned negative for variants in BRCA1/BRCA2.

However, a website that explains what customers can learn from 23andMe’s reports acknowledges they “do not cover all possible genetic variants that could influence risk for [certain health] conditions and that other nongenetic factors — such as environment and lifestyle — can also influence risk for these conditions.”


Could it be that Donna remained genetically at risk for breast cancer?

There are more than 1,000 variants in BRCA1/BRCA2 that can predispose a person to cancer.

Last year, the FDA permitted 23andMe to market its Personal Genome Service Genetic Health Risk Report, which uses genotyping to evaluate three of those known pathogenic variants. These variants are most common among individuals of Ashkenazi Jewish descent.

Consumers may not realize a negative result only refers to these three variants in BRCA1/BRCA2, or that the many other factors aside from genetics that influence cancer risk are not included in the DTC testing interpretation.

Skepticism also remains about the accuracy of DTC testing.

Tandy-Connor and colleagues used a laboratory-developed test from Ambry Genetics to evaluate samples that had previously identified genetic variants reported in raw data after DTC testing from multiple vendors.

The laboratory-developed test, based on Sanger and next-generation sequencing, could not confirm 40% of variants — in eight different genes — identified through DTC testing.

Aside from the high rate of false positives, this study identified discrepancies in variant interpretation from the DTC test results, although it is typical practice for DTC test results to be based upon population references.

For true personalization, an individual comprehensive risk evaluation should be conducted.

Risk evaluation should include a genetics counselor or a certified medical geneticist. This individual could help determine whether the genetic test should be performed, and also assist with interpretation of results in the context of personal and family history.

Pharmacogenetics DTC testing

In October, the FDA approved the first DTC pharmacogenetics test for over-the-counter use to identify 33 inheritable variants in drug disposition proteins that affect 50 drugs.

This test — also manufactured by 23andMe — is not yet available in the United States; however, it is anticipated that consumers will be able to purchase it through local retailers and online.

A similar DTC pharmacogenomics test available in the United Kingdom uses a panel that evaluates variants of 10 genes.

A study by Lu and colleagues showed the DTC pharmacogenetic results provide an incomplete clinical picture and do not assess all alleles relevant to a diversity of ethnicities.

For example, variants in CYP2C9 that are most common among individuals of African and East Asian ancestry (eg, CYP2C9*8 and CYP2C9*11) are not tested as part of the DTC panel. These variants are found in about 5% of individuals of African ancestry and are virtually absent in Caucasian populations.

The authors concluded there should be more consideration to what tests should be reported, and that differences in frequency of alleles make it difficult to implement a DTC pharmacogenetic test across all ethnicities.


The investigators called for increasing awareness about DTC pharmacogenetic testing, including the risk of providing medical information that is not communicated through a health care professional.

Clinical controversies

The question of whether a consumer is fully informed about risks is central when considering the omission of a health care professional from the genetic testing process.

The Genetic Information Nondiscrimination Act (GINA) protects patients against coverage discrimination from health insurance companies or employers based on genetic data.

However, this federal law has significant limitations of which consumers should be aware. For example, it does not apply to long-term care or life insurance. Also, it only applies to employers with 15 or more employees.

Additionally, GINA places the burden of proof on the person alleging discrimination to prove that their genetic information was misused.

It also is unclear whether DTC achieves its goal of empowering consumers to take charge of their health.

Gray and colleagues conducted a study of 1,042 consumers who underwent DTC testing and completed baseline and 6-month surveys. At 6 months, study participants whose results showed elevated cancer risk estimates were not significantly more likely to change their exercise, diet, advanced care planning or cancer screening behaviors than those whose results indicated average or reduced risk.

Privacy concerns also persist. These include awareness of vendor use of genetic data and the risk for privacy breach of confidentiality for family members of the proband who did not consent to genetic testing.

Given her family history, Donna was advised to seek clinical molecular genetic testing and genetic counseling. This led to identification of a pathogenic variant in BRCA2.

Donna, a hypothetical patient inspired by a true story, ultimately received care that effectively personalized her true risk. Others may not seek care as she did, and concern remains about the possibility that one could misunderstand their genetic risk. This case illustrates the potential for false reassurance.

Provider awareness

It is important that providers develop awareness of DTC tests, including their limitations and implications for care delivery.

However, the prospect of receiving unsolicited genomic results raised multiple concerns in a survey of 25 pediatric/adult primary care, cardiology and oncology physicians conducted by Pet and colleagues.

Survey respondents indicated that only actionable genomic results should be returned to patients and providers. Compounding these feelings were underlying concerns that many physicians would not know how to respond to unsolicited genomic results, and that this would limit actionability.

Other studies have suggested that providers generally feel unprepared and undertrained to respond to unsolicited genomic results, which likely will be encountered as the DTC market expands.


Resources exist to increase provider training in precision medicine.

For example, many institutions and organizations — such as University of Colorado Skaggs School of Pharmacy and the American Society of Health-System Pharmacists — offer certificate programs in pharmacogenomics. Other options include University of Florida’s graduate certificate program in precision medicine.

‘Dichotomous stance’

The same day the FDA granted approval for the first DTC pharmacogenomics test, it issued a warning letter cautioning that most pharmacogenetics devices have not been evaluated by the FDA, and that using such tests may lead to harm.

This dichotomous stance perplexed the health care community.

On one hand, a DTC test received FDA approval with the caveats that any medical decisions should be made only after discussing results with a licensed health care provider and that results have been confirmed using clinical pharmacogenetic testing. However, the only FDA-approved pharmacogenetics test to date is the DTC in vitro diagnostic.

Further, the FDA sent a warning letter to Inova Genomics Laboratory in which it states “the relationship between CYP2C19 genotype and drug response to escitalopram and sertraline is not established.”

However, these drug-gene pairs are categorized as actionable by the Clinical Pharmacogenetics Implementation Consortium (CPIC), comprised of pharmacogenetic experts who curate data and levels of evidence generated by pharmacogenomic studies for a given gene.

CPIC provides guidelines on how to translate genetic results into actionable prescribing decisions.

In response to the FDA warning letter to Inova Genomics Laboratory, CPIC issued a statement highlighting that CPIC guidelines for selective serotonin uptake inhibitors identify CYP2C19 phenotypes as “actionable” for escitalopram and sertraline.

Further, the mechanism of gene-drug interaction is pharmacokinetic in nature. This is analogous to adjustments made in response to hepatic or renal dysfunction, which often are supported with mechanistic evidence rather than clinical trial data.

These FDA actions are perplexing to the health care community in the context of the regulatory history associated with laboratory-developed tests (LDTs), as well.

LDTs are in vitro diagnostics intended for clinical use and designed, manufactured and used within a single laboratory. The FDA traditionally has not exercised regulation of LDTs, although it has maintained that it has authority to do so.

Uncertainty about FDA oversight of LDTs has been evident since the 1970s.

In its warning letter, the FDA stated: “FDA has not created a legal ‘carve out’ for LDTs such that they are not required to comply with the requirements under the Act that otherwise would apply. FDA has never established such an exemption. As a matter of practice, FDA, however, has exercised enforcement discretion for LDTs, which means that FDA has generally not enforced the premarket review and other FDA legal requirements that do apply to LDTs. Although FDA has generally exercised enforcement discretion for LDTs, the agency always retains discretion to take action when appropriate, such as when it is appropriate to address significant public health concerns.”


Thus, the longstanding issue of lack of clarity on FDA regulation of LDTs once again has been raised.


It is important to keep in mind when working with patients that DTC tests are not diagnostic. Nevertheless, DTC results should be pursued only from a CLIA- and CAP-certified lab.

There may be potential for false positives and misclassified results with DTC tests, and these genetic results are based on population data. True personalization requires a comprehensive risk evaluation.

Further, GINA has significant limitations of which patients must be aware. Lastly, it is extremely important that health care providers become educated about DTC tests. Health care providers should be able to respond to patient inquiries in the context of full understanding of the DTC platform utilized, as well as its limitations.


23andMe. What health-related information can I learn from 23andMe? Available at: customercare.23andme.com/hc/en-us/articles/115013843028-What-health-related-information-can-I-learn-from-23andMe. Accessed on May 21, 2019.

ACMG Board of Directors. Genet Med. 2016;doi:10.1038/gim.2015.190.

BIS Research. Global direct-to-consumer genetic testing (DTC-GT) market: Focus on direct-to-consumer genetic testing market by product type, distribution channel, 15 countries mapping and competitive landscape — analysis and forecast, 2019-2028. Available at: bisresearch.com/industry-report/direct-to-consumer-genetic-testing-market.html. Accessed on May 21, 2019.

GenomeWeb. FDA actions on PGx testing confuse genetic industry players. Available at: www.genomeweb.com/regulatory-news/fda-actions-pgx-testing-confuse-genetic-industry-players#.XOL7achKjcu. Accessed on May 20, 2019.

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Tandy-Connor S, et al. Genet Med. 2018;doi:10.1038/gim.2018.38.

The PharmGKB Blog. CYP2C19 testing may assist with prescribing sertraline and escitalopram. Available at: pharmgkb.blogspot.com/2019/04/cyp2c19-testing-may-assist-with.html. Accessed on May 20, 2019.

U.S. FDA. Direct-to-consumer tests. Available at: www.fda.gov/medical-devices/vitro-diagnostics/direct-consumer-tests. Accessed on May 20, 2019.

U.S. FDA. FDA authorizes first direct-to-consumer test for detecting genetic variants that may be associated with medication metabolism. Available at: www.fda.gov/news-events/press-announcements/fda-authorizes-first-direct-consumer-test-detecting-genetic-variants-may-be-associated-medication. Accessed on May 20, 2019.

U.S. FDA. The FDA warns against the use of many genetic tests with unapproved claims to predict patient response to specific medications: FDA safety communication. Available at: www.fda.gov/medical-devices/safety-communications/fda-warns-against-use-many-genetic-tests-unapproved-claims-predict-patient-response-specific. Accessed on May 20, 2019.

For more information:

Jill S. Bates, PharmD, MS, BCOP, FASHP, is oncology precision therapeutics pharmacist and director of the PGY2 oncology pharmacy residency program at University of North Carolina Medical Center, as well as associate professor of clinical education at UNC Eshelman School of Pharmacy. She also is a HemOnc Today Editorial Board Member. She can be reached at batesjill@gmail.com.

Disclosure: Bates reports no relevant financial disclosures.