Panel Testing Is Not a Panacea

Panel testing for inherited cancer predisposition is rapidly becoming the norm. Evidence is mounting that many of the cancer-associated genes have substantially overlapping, and often clinically indistinguishable, phenotypes. Next-generation sequencing technologies now allow for analysis of many genes simultaneously, and testing platforms are easily and inexpensively expanded with each new gene discovery. Therefore, there is an undeniable economical advantage to panel testing, but the extent of the clinical advantage remains elusive. As such, many recent studies have explored this issue. In an article accompanying this editorial, Thompson et al use a case-control approach to assess mutation frequency in 18 genes that were specifically included due to an association with increased risk for breast cancer. Beyond BRCA1 and BRCA2, a significant excess of mutations was also detected in the PALB2 and TP53 genes. By comparison, mutations in NBN and RAD50 were actually more prevalent among controls than cases. Overall, the vast majority of genes included in their study, which are on current commercial breast cancer panels, failed to explain most of the excess genetic risk beyond BRCA1 and BRCA2. In another article accompanying this editorial, Tung et al used a commercial laboratory-designed pan-cancer panel to assess the frequency of mutations in 488 patients with breast cancer. The participants were unselected for age, family history, ethnicity, or cancer subtype, but they had agreed to participate in research DNA banking. In this sequential series, which comprised 70% of eligible patients seen at a single institution, 30 patients (6.1%) had a BRCA1 or BRCA2 mutation, 20 (4.1%) had a mutation in another breast cancer-associated gene, and 4 (0.8%) had a mutation in a non–breast cancer-associated gene. All BRCA1 and BRCA2 mutations were detected in patients who had already been tested clinically or who had met National Comprehensive Cancer Network criteria for testing, which is reassuring. However, clinical factors used to predict a BRCA1 or BRCA2mutationwere unable to predict a mutation in non-BRCA1/2 genes. Much of the previous data on panel testing is laboratory derived and subject to significant bias. Specifically, laboratory data are often evaluated using a case-only design, and the reported cancer history is highly dependent on the person completing the test requisition form (who may or may not be a clinician, and who may or may not be experienced in genetics). Existing clinic-based reports, including the one by Tung et al, are also case only in design. Therefore, the current study by Thompson et al is more robust, because all of the cases were evaluated by cancer genetics professionals, and there is a direct comparison with a control population that is enriched for older age. In addition to the prevalence data, Thompson et al emphasize important ethical and medicolegal issues, including the risk of over-attributing causality to lowto moderate-penetrant genes. As such, clinical users of panels must understand the widely varying clinical implications of each tested gene. Clinical genetics providers are essentially in a reactionary position, having to modify their testing andmanagement approach on the basis of laboratory-developed tests rather than being in a position to lead test development. Many of the genes included in inherited cancer predisposition panels are based on molecular pathway inference rather than on actual clinical data, and have yet to be confirmed in the general population. For this reason, clinical results are accumulating much faster than the ability to meaningfully interpret and apply those results, causing a conundrum for clinicians and researchers. Consequently, both Thompson et al and Tung et al advocate for continued widespread clinical panel testing to identify more high-risk families, but also to provide a data source to better understand the significance of genes that are currently not well characterized. Admittedly, this blurs the lines between clinical practice and research, and the authors also caution that great care must be exercised when applying molecular findings to clinical management. One could argue, then, that large panel testing on a clinical basis may eventually benefit society as a whole. However, it currently has potential to pose considerable risk to the individual patient. Highly trained genetics providers are struggling with not only how to classify various molecular findings, but also with how—or even if—to use them to influence medical management of the patient and family. In essentially all areas of medicine, specialization is critical to ensure proper patient care, and genetics is no exception. Even within genetics, most providers are subspecialized, focusing on a particular aspect (eg, prenatal, metabolic, cancer, cardiovascular, and so on). Unfortunately, genetic testing is often mistakenly viewed as just a simple blood test that yields either a positive or a negative result. However, cancer-associated genes, in particular, are just one part of multifactorial (and even polygenic) predisposition to disease, and cannot necessarily be viewed as an actual diagnosis. As such, challenges that are unique to genetic medicine, and possibly overrepresented in cancer genetics, include identification of mutations in genes that are inconsistent with the patient/family history, high rates of variants of uncertain significance, and