'Brave New World' of Genetic Cancer Susceptibility Testing

Roxanne Nelson

September 03, 2015

"A brave new world is emerging for genetic cancer susceptibility testing," and there is no question that this type of testing has provided clinical benefit to a small segment of the population. But there are also complexities within this field, and there are many areas where the information being uncovered is not fully understood, warn experts discussing the new developments in an editorial published online August 31 in the Journal of Clinical Oncology.

There is a proliferation of these tests now available. Perhaps the best known example is testing for BRCA1 and BRCA2 genes, which increase the risk for breast and ovarian cancer. Another example is Pathway Genomics, which offers testing to analyze more than 100 different markers for prostate cancer, melanoma, other malignancies, and noncancer conditions. But there are many others, marketed by companies that include Myriad Genetics, Ambry Genetics, Invitae Corp, Navigenics, deCODE genetics, Illumina, and Gene by Gene.

The editorialists writing about this "brave new world" come from the highest offices of the American Society of Clinical Oncology (ASCO): Julie M. Vose, MD, is current president; Peter Paul Yu, MD, is immediate past president; and Daniel Hayes, MD, will be president in 2016/17.

The editorial was written to accompany an updated policy statement on genetic and genomic testing issued by ASCO.

The update highlights the way new technologies are changing the assessment and identification of cancer susceptibility and provides recommendations on how these new technologies can be appropriately used in clinical practice.

"The sequencing and mapping of the human genome, one of science's greatest modern feats, has launched an age of tremendous discovery and hope in the fight against cancer," Dr Vose said in a statement.

"As cancer diagnosis and treatment are becoming more genetically driven, new opportunities and questions are emerging about screening for hereditary cancers," she noted. "ASCO is releasing this updated policy statement at this critical juncture to ensure that all interested parties thoughtfully consider these concerns as the future of genetic and genomic testing for cancer susceptibility unfolds."

ASCO's first policy statement on genetic testing was issued in 1996. That was followed by updates in 2003 and 2010 in response to continuing developments in the field. This year's update was developed to address the impact of advances in this area on oncology practice.

"New technology is introducing great complexity" and presenting significant implications for patients, providers, policy makers, and the entire healthcare system, the ASCO team responsible for the update writes.

In particular, they point to next-generation sequencing (NGS), which can be used to catalogue large amounts of DNA much more quickly and at a lower cost than traditional methods.

For a cancer patient, NGS makes it feasible to find DNA sequence variations within a tumor, possibly defining "therapeutic targets," which might improve outcomes.

"Enormous Challenge" Remains

Understanding which genetic variations are benign and which are deleterious...remains an enormous challenge.

However, the editorialists caution that not all genetic variations by themselves are pathogenic. "Many mutations still remain indeterminate for their role in carcinogenesis and are called variants of uncertain significance," they point out. " Understanding which genetic variations are benign and which are deleterious drivers of disease expression remains an enormous challenge."

Although data for some specific genes strongly support the identification of deleterious mutations so that affected individuals can take appropriate action, it is not clear for other putative susceptibility genes, and there is far less evidence that they might affect cancer risk substantially, or at all, they explain.

The situation becomes even more complicated with NGS, which allows for "simultaneous sequencing of multiple genes that are genetic hot spots with known cancer associations, the whole exome, and even the entire genome of a patient," they add.

More is not necessarily better for the patient because the more genomic data that are generated, the greater the uncertainty about their clinical meaning. This overload of information, along with its undetermined analytic and clinical utility, could result in unnecessary fear and anxiety on the part of the patient, they note, as well as possible interventions that are inappropriate.

Finally, the editorialists emphasize that NGS is only an example of the rapidly expanding technology; whole-exome sequencing and whole-genome sequencing are on the horizon. "Increasingly, we will be the recipients of data that we did not anticipate or, perhaps, even seek to know," they write. "Accordingly, we will be in the uncomfortable position of reacting to that data on the basis of an immature and incomplete understanding of what that data mean."

As technology moves forward, they conclude, "robust discussions" are needed among all stakeholders to ensure that all perspectives are heard and that "genetic cancer susceptibility services are comprehensive and patient centric."

The updated policy statement identifies five key areas that need to be addressed.

Key Areas to Be Addressed
Germline Implications of Somatic Mutation Profiling: ASCO calls for further research to develop best practices for the delivery of incidental and secondary germline findings, and encourages research aimed at improving understanding of patient preferences, optimal pretest education and informed consent, and outcomes that involve the patient, provider, healthcare system delivery, and cost. ASCO also recommends that laboratories that conduct secondary analyses develop mechanisms to report only somatic results for patients who decline to receive germline findings.
Multigene Panel Testing for Cancer Susceptibility: Providers with particular expertise in cancer risk assessment should be involved in ordering and interpreting multigene panels that include genes of uncertain clinical utility and those suggested by the patient's personal and/or family history. ASCO encourages research to delineate the optimal use of panel-based testing, the development of evidence-based practice guidelines as data continue to emerge, and the education of providers on the challenges of using these tests.
Quality Assurance in Genetic Testing: ASCO recommends appropriate regulation of tests that detect inherited genetic variants and the support of a risk-based approach to US Food and Drug Administration regulation for laboratory-developed tests and commercial tests, but in a manner that does not compromise innovation or limit patient access to testing. High-quality standards should be adopted that allow providers and patients to understand the accuracy, benefits, and limitations of genetic tests conducted by individual laboratories.
Education for Oncology Professionals: ASCO recommends continued education for oncologists and other healthcare professionals in cancer risk assessment and the management of individuals with inherited predisposition to cancer. It also recommends that oncology training programs develop a set of core skills for new trainees and ensure adequate time for achieving these skills.
Access to Cancer Genetics Services: There is a need for coverage policies that support access to cancer risk assessment and prevention services for individuals who are suspected to be at increased genetic risk. ASCO opposes any payment policies that have the potential to negatively affect the care of cancer patients by serving as a barrier to the appropriate use of genetic testing services.


Some of the policy statement authors and editorialists have disclosed relationships with industry, including companies that conduct genetic testing.

J Clin Oncol. Published online August 31, 2015. Policy statement, Editorial


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