Genetic Cancer Susceptibility Testing: Increased Technology, Increased Complexity

The application of precision medicine to clinical oncology will evolve as the technology that underlies precision medicine advances. Indeed, as seen in the American Society of Clinical Oncology (ASCO) policy statement update (on genetic and genomic testing for cancer susceptibility) published in this issue, the increase in genetic sequencing capability combined with the decrease in the cost of testing have altered both regulatory policy and clinical practice and have led to this ASCO policy statement update. Over the past few decades, inherited germline genetic differences among individuals that substantially increase a person’s susceptibility to cancerhavebeenidentified.Well-knownexamplesofclinically important genetic variations (more commonly called mutations) are found in genes such as BRCA1/2 (breast cancer), MSH (colon cancer), RB, and P53 (retinoblastoma and Li-Fraumeni syndrome). Commercially and, more recently, noncommercially available tests are frequently ordered for selected individuals who have a reasonably high chance of harboring mutations in these and other genes, to determine if such individuals and their medical team should implement additional risk mitigation strategies beyond standard of care for the screening or prevention of the associated malignancies. The ASCO policy update provides guidance on when these tests should be ordered and how to interpret them. There is no question that these tests have provided clinical benefit to a small segment of our population. Indeed, there have been calls for much wider application of germline genetic susceptibility testing and even a recommendation that all women should have BRCA1/2 testing, regardless of family history. However, the immense heterogeneity of the human genome, both within and across races and ethnicities, gives rise to many genetic variations that are not by themselves necessarily pathogenic. Many mutations still remain indeterminate for their role in carcinogenesis and are called variants of uncertain significance (VUS). Understanding which genetic variations are benign and which are deleterious drivers of disease expression remains an enormous challenge. The large number of mutations classified as VUS, the methodologic weaknesses inherent to the analysis whereby VUS mutations are reclassified as pathogenic or benign mutations, and the unknown but certain existence of unidentified germline mutations that increase cancer susceptibility all contribute to a degree of ambiguity that exists in genetic counseling of patients about the inherited risk of cancer development. Indiscriminate germline testing in the population will identify far more VUS than established deleterious mutations, which leads to major concerns about unnecessary intensive screening and preventive approaches, including prophylactic surgeries, as well as increased anxiety levels among those who carry them. Although the ASCO guidelines panel recognizes these concerns, the panel continues to recommend a relatively cautious and selective approach, albeit one that is expanded from the previous guideline. However, a brave new world is emerging for genetic cancer susceptibility testing. The previous comments relate to analysis of specific genes that are known to be involved in tumor suppression and for which data strongly support identification of deleterious mutations so that affected individuals can take appropriate actions. Over the past decade, many otherputativesusceptibilitygeneshavebeenidentified,andthereis far less evidencethat thesegenes increaseanindividual’srisksubstantiallyoreven at all. Several commercial entities have now begun to include these genes in panel assays that are bundled with genes known to be important, such as BRCA1/2. On the surface, inclusion of these other genes would seem to offer added value. However, because the clinical utility of the information provided is quite uncertain, the results are likely to lead to false alarms for patients and inappropriate clinical actions. The situation is becoming even more complicated. After the first report of cloning of the human genome, rapid technologic advances have led to exponential reductions in the time and cost required to comprehensively sequence an individual’s genetic profile. Such an approach, designated massively parallel sequencing or nextgeneration sequencing (NGS), may supplant single-gene or even multiple-gene panel assays for genetic susceptibility testing. NGS allows 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. However, because of the vast heterogeneity of human genetics, the more genomic data is generated, the greater is the uncertainty about the clinical meaning of this data. The abundance of data of undetermined analytic and clinical utility may result in unnecessary patient fear and anxiety as well as, possibly, the adoption of inappropriate risk mitigation strategies. As exciting as these technologies are, one must be cognizant that different technologies for NGS are not identical. The accuracy of NGS is dependent on the multiplicity or redundancy with which the sample is analyzed, known as depth of coverage, and on other factors that are reviewed in the ASCO policy statement. These factors determine the analytic validity of the test. In addition, the clinical validity (whether JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 31 NOVEMBER 1 2015