One fourth (23.3% [n=156]) of patients who underwent genetic testing had a clinically relevant change in management, which includes those who tested positive for a pathogenic mutation and those who tested negative for a known familial mutation. Of those testing positive for a mutation, 96% (n=111; female patients=95% [n=95]; male patients=100% [n=16]) had an increase in surveillance, clinical management, or both, as depicted in Figure 3. Of note, 50% of these patients had a personal history of cancer and had been adhering to prior recommendations of increased management specific to their diagnosis. Therefore, the number of clinical management changes offered illustrated in Figure 3 is relatively lower than it would be had all individuals been unaffected.
Of the five patients with positive mutations without an increase in management, two had deleterious mutations in BARD1. The National Comprehensive Cancer Network does not yet have specific recommendations for the clinical management of this mutation, and thus, at the time of counseling, there were no specific recommendation provided by our genetic counselors other than those guided by the family history alone. Two additional patients with ATM and BRIP1 mutations, respectively, did not have a change in management as a result of their personal history of cancer. These two patients had already undergone the clinical recommendations as per National Comprehensive Cancer Network guidelines. Finally, the fifth patient had a RAD50 mutation and did not have a change in management because the genetic counselors did not feel as though this mutation explained the patient's personal and family history of cancer.
There were 45 participants (6.7% of those tested) who tested negative for a known familial mutation. Based on the negative results, all of these individuals had a decrease in management recommendations from what would have been suggested had genetic testing not occurred.
At least one variant of uncertain significance was found in 30.1% (n=202) of those tested and both a variant of uncertain significance and deleterious mutation were found in 3% (n=20) of those tested. Distribution of the variants identified is depicted in Figure 4. All individuals with a variant of uncertain significance or a mutation in a moderate penetrance gene were encouraged to participate in one of the large, nationwide prospective registries (ie, Evidenced-based Network for the Interpretation of Germline-mutant Allele and Prospective Registry of Multiplex Testing).
This study demonstrates that 1) a significant number of non-BRCA mutations are identified on panel testing that previously would have been missed on targeted testing and 2) the majority of patients found to have a deleterious mutation are diagnosed with a clinically actionable finding for which National Comprehensive Cancer Network guidelines are available for surveillance and cancer prevention. Interpreting the complex results from panel testing, and providing a means for follow-up and surveillance of those with known deleterious mutations, variant of uncertain significance, and patients from at-risk families, emphasizes the important role that cancer genetic specialists play in management in conjunction with the primary care provider.
Risk-appropriate panel testing often reveals mutations that would have been missed by BRCA1 or 2 or targeted testing alone. In our study, 7.3% of the testing population was found to have a non-BRCA1 or 2 mutation, which represented 75% of the participants who had a positive panel test and 42% of those with any positive deleterious mutations identified in the study. This data contribute to the growing body of knowledge supporting panel testing. In the largest study to date, including 65,057 patients, Couch et al7 confirmed an increased risk of breast cancer in patients with pathogenic mutations in genes including ATM, BARD1, CHEK2, PALB2, and RAD50. The yield of non-BRCA1 and 2 mutations in our cohort (7.3%) exceeds that of previous cohorts.6,7 This may be the result of an increased number of genes on more recent panels or differences in indications for testing.
Panel testing can provide critical information when imperfect family histories exist as a result of gaps in knowledge, limited family structure, incorrectly communicated histories, or for individuals whose history does not fit neatly into a single cancer syndrome.8 Many individuals harboring important cancer risk genes are overlooked because they would not meet criteria for testing under traditional single-gene and syndrome-focused approaches.8 With increasing frequency of risk-appropriate panel testing, we will gain both a better understanding of the penetrance of lesser known mutations and superior mutation-based management guidelines. Additionally, panel testing allows for efficient use of the patient's sample and decreases the chances of testing fatigue for both the patient and health care provider.9
Most known deleterious mutations have National Comprehensive Cancer Network guidelines for surveillance and management; thus, the majority of those testing positive in our study had well-documented increases in surveillance or management. The rate of management changes for mutations carriers in our study was greater than a previous study,8 perhaps reflecting differences in inclusion criteria for the study, evolving National Comprehensive Cancer Network guidelines, or both. Although some of the benefits of increased surveillance for certain malignancies, specifically ovarian, remain controversial, many have been demonstrated to improve survival in those with significant risk.10,11 Furthermore, with the discovery of mutations, participants are often encouraged to engage additional family members in genetic testing, another actionable outcome of panel testing.8 Those who tested negative for known familial mutations were able to decrease the amount of intervention they would have had without testing if solely based on family history, preventing potentially unnecessary testing or prophylactic measures.
Although it is evident from our study and other reports on panel testing, increasing the number of genes tested increases variant of uncertain significance identification. Thousands of variants have been recorded to date and have presented challenges because the reclassification of variants is complicated and the data exploring the reclassification are sparse. However, there is evidence to suggest that with continued research and a standardized practice for reclassification of variants of uncertain significance, we can successfully refine genetic testing. Using BRCA1 and 2, two of most highly studied genes, as a model for the reclassification, the variant of uncertain significance rate from 2002 to 2013 declined from 12.8% to 2.1%.7 These high rates of variants of uncertain significance identified in our study are not dissimilar to that seen in the early years of BRCA testing and will be further clarified with more prospective data.12 The challenge is in creating constructs by which laboratories and academic groups share their data and develop a universal means of classification for distinguishing deleterious mutations from their benign variant counterparts.12 Therefore, it is integral that patients identified to have a known deleterious mutation or a variant of uncertain significance continue to be followed at a center that is committed to following the ongoing research in the field and altering management accordingly.13
With the ever-increasing complexity of cancer genetic counseling and testing and the rapid changes in management guidelines, it is becoming a challenge for primary care providers to remain up to date on this topic. As testing becomes more comprehensive, the counseling and risk assessment become more time-consuming, creating more strain on health care providers. Obstetrician–gynecologists play an important role in identifying at-risk women, educating them about the availability of genetic testing service and referring them to proper licensed genetic counselors or cancer genetic experts for both pretest and posttest counseling, as outlined by the American Society of Clinical Oncology policy.9 These health care providers carry the responsibility of selecting the most appropriate testing and serving as educators and liaisons to the treating physicians to provide the most current and personalized management. Most academic institutions have certified genetic counselors available as part of their oncology services. Community and rural practices may access cancer genetic specialists through either telemedicine consultation with academic centers or directly through the testing company.
The results of this study should be interpreted in the context of certain limitations. These include the bias inherent in a single-institution retrospective analysis, the lack of uniformity in patient presentation to the clinic, and the variability in test and laboratory selection. We attempted to overcome these limitations by adhering to National Comprehensive Cancer Network guidelines for clinical management at the time of mutation diagnosis and we continue to monitor updates and evolving surveillance guidelines within the field. Also, this study focused on process measures such as change in management rather than clinical outcomes. Prospectively following the women for occurrence of cancer is a potential area for further investigation. Finally, this study did not assess any potential negative effect of counseling and testing such as emotional or financial concerns, although others have rigorously evaluated the psychologic effects of genetic testing.14
Panel testing for hereditary cancer syndromes is a viable means of identifying individuals at risk for developing cancer. Results from this testing are associated with clear actionable management strategies while reducing the possibility of unnecessary interventions in those deemed average risk. Given that many women access much of their care through their obstetrician–gynecologist, it is imperative that health care providers understand the utility of this dynamic testing and, during routine visits, assess the need for further risk assessment and counseling. However, considering the rapidly evolving nature of this field, it is integral that counseling, test selection, interpretation of test results, and posttest counseling occur among oncology and genetics colleagues who can provide the most up-to-date recommendations.
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© 2018 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
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