BRCA1 and BRCA2 genes are associated with 3–6% of female breast cancers1 and 14% of ovarian cancers.2 An increasing number of genes with links to hereditary cancer are being identified as are novel treatments targeting these specific genetic mutations. In recent years, genetic testing using an extended panel of cancer predisposition genes, often referred to as panel testing, has gained significant momentum in identifying actionable genetic mutations. In certain populations such as Ashkenazi Jews, studies have already confirmed that most findings from genetic panel testing have yielded clinically relevant management changes.3
Use of panel testing has improved our understanding that non-BRCA mutations are present in a significant proportion of patients with hereditary cancer.4 Panel testing, as opposed to targeted testing, may help reveal the contribution to genetic risk when multiple genes are involved or when a patient's personal or family history is inconsistent with a known syndrome. Application of mutation-based guidelines such as those provided by the National Comprehensive Cancer Network have helped target precise clinical management to the mutations identified. Nevertheless, concerns about panel testing remain, including the potential for misuse of information and the lack of clinical recommendation actionability for some results. As the health care providers of comprehensive primary care for women, obstetrician–gynecologists have a pivotal role in the initial risk assessment and education of patients regarding testing opportunities and appropriate referrals.5
Prior studies have reported on the prevalence of various cancer risk mutations; however, few have addressed if the findings are associated with changes in clinical management.6 This retrospective study describes the prevalence of mutations among our referral population based on testing modality and the resulting guideline-based management changes.
MATERIALS AND METHODS
Institutional review board approval from The George Washington University School of Medicine was obtained to perform a retrospective chart review of participants referred to the Ruth Paul Hereditary Cancer Program for genetic counseling, testing, or both. Included patients participated in a counseling session with one of the program's genetic counselors between January 1, 2015, and December 29, 2016. Participants were identified as at-risk based on a personal or family history of breast, ovarian, or other cancer by their health care provider or by self-referral. All personal and family history data were ascertained by certified genetic counselors and entered into the program's clinical registry. All participants met current National Comprehensive Cancer Network criteria for further genetic risk evaluation for hereditary cancer (Box 1). Patients who met additional criteria and consented to the procedure underwent genetic testing (Box 2). Genetic test selection included either single-gene mutation screening, BRCA1 or 2 mutation screening, or an expanded mutation panel screening (referred to as panel testing) and was up to the discretion of the certified genetic counselor. Decision-making is individualized and guided by the participant's pedigree, ethnicity, and patient preference among other factors.
National Comprehensive Cancer Network Guideline Version 2015: Hereditary Breast, Ovarian, or Breast and Ovarian Cancer Genetic Assessment Criteria for Further Genetic Risk Evaluation
An individual with a cancer diagnosis meeting any of the following:
- • A known mutation in a cancer susceptibility gene within the family
- • Early-age-onset breast cancer
- • Triple negative (ER−, PR−, HER2−) breast cancer at 60 y old or younger
- • 2 breast cancer primaries in a single individual
- • Breast cancer at any age and
- ○ 1 or more close blood relatives with breast cancer at 50 y old or younger, or
- ○ 1 or more close blood relatives with invasive ovarian cancer at any age, or
- ○ 2 or more close blood relatives with breast cancer, pancreatic cancer, or both at any age, or
- ○ From a population at increased risk
- • Following (especially if early onset): pancreatic cancer; prostate cancer (Gleason score 7 or higher); sarcoma; adrenocortical carcinoma; brain tumors; endometrial cancer; thyroid cancer; kidney cancer; dermatologic manifestations, macrocephaly, or both; hamartomatous polyps of the gastrointestinal tract; diffuse gastric cancer (can include multiple primary cancer in the same individual)
- • Invasive ovarian cancer
- • Male breast cancer
An individual with no personal history of cancer but with a family history of any of the following:
- • A known mutation in a cancer susceptibility gene within the family
- • 2 or more breast cancer primaries in a single individual
- • 2 or more individuals with breast cancer primaries on the same side of the family
- • 1 or more invasive ovarian cancer primaries
- • 1st- or 2nd-degree relative with breast cancer at 45 y old or younger
- • Personal, family, or both history of three or more of the following (especially if early onset): pancreatic cancer; prostate cancer (Gleason score 7 or higher); sarcoma; adrenocortical carcinoma; brain tumors; endometrial cancer; thyroid cancer; kidney cancer; dermatologic manifestations, macrocephaly, or both; hamartomatous polyps of the gastrointestinal tract; diffuse gastric cancer (can include multiple primary cancers in the same individual)
- • Male breast cancer
National Comprehensive Cancer Network Guideline Version 1.2015: Hereditary Breast, Ovarian, or Breast and Ovarian Cancer Syndrome Testing Criteria
1 or more of the following criteria warrants further genetic testing and management:
- • Individual from a family with a known deleterious BRCA1 or BRCA2 mutation or other cancer susceptibility gene
- • Personal history of breast cancer+1 or more of the following:
- ○ Diagnosed at 45 y old or younger
- ○ Diagnosed at 50 y old or younger with:
- ▪ An additional breast cancer primary
- ▪ 1 or more close blood relative with breast cancer at any age
- ○ Diagnosed at 60 y old or younger with a:
- ▪ Triple negative breast cancer
- ○ Diagnosed at any age with:
- ▪ 1 or more close blood relatives with breast cancer at 50 y of age or younger or
- ▪ 1 or more close blood relatives with invasive ovarian cancer at any age, or
- ▪ 2 or more close blood relatives with breast cancer, pancreatic cancer, or prostate cancer (Gleason 7 or higher) at any age, or
- ▪ A close male blood relative with breast cancer
- ▪ For an individual of ethnicity associated with higher mutation frequency (eg, Ashkenazi Jewish), no additional family history may be required
- ○ Personal history of invasive ovarian cancer
- ○ Personal history of male breast cancer
- • Personal history of prostate cancer (Gleason score 7 or higher) at any age with one or more close blood relative with breast (50 y old or younger), invasive ovarian, pancreatic or prostate cancer (Gleason score 7 or higher), or all of these at any age
- • Personal history of pancreatic cancer at any age with one or more close blood relative with breast (50 y old or younger), invasive ovarian, pancreatic, or all of these at any age
- • Personal history of pancreatic cancer and Ashkenazi Jewish ancestry
- • Family history only (significant limitations of interpreting test results for an unaffected individual should be discussed)
- ○ 1st- or 2nd-degree blood relative meeting any of the above criteria
- ○ 3rd-degree blood relative who has breast cancer, invasive ovarian cancer, or both and who has two or more close blood relatives with breast cancer (at least one with breast cancer at 50 y old or younger), invasive ovarian cancer, or both
The patients' DNA was sequenced at one of several Clinical Laboratory Improvement Amendment-approved commercial laboratories specializing in cancer genetic testing. Clinical management changes after discovery of positive deleterious mutations in individuals were based on current National Comprehensive Cancer Network guidelines. Decisions about management recommendations and changes were made collaboratively by the genetic counselors, medical oncologists, gynecologic oncologists, and surgical providers. No clinical management changes were made for variants of uncertain significance beyond changes that would have been recommended based on personal or family history alone. Individuals found to have a variant of uncertain significance were told that they would be informed of any reclassification of that genetic mutation when available.
A χ2 test was used to compare proportion of panel and nonpanel testing in 2015 compared with 2016.
Eight hundred twenty-two patients (number of male patients=71) underwent genetic counseling between January 2015 and December 2016. Individuals were referred to the Ruth Paul Hereditary Cancer Program from the following types of clinics: breast surgery (27.6%), hematology oncology (26.6%), internal medicine (15.4%), obstetrics and gynecology (8.1%), gynecology–oncology (2.5%), surgery (1.8%), gastroenterology (0.9%), radiology (1%), and other (0.4%). Additionally, 12.1% were self-referred and 3.6% were referred by friends or family. Reasons for referral included family history (n=389 [47.3%]), personal and family history (n=253 [32%]), and personal history alone (n=170 [20.7%]). Additionally, 12.2% (n=100) of those presenting for counseling had a previously known family mutation. Of those counseled, 81.4% (n=670; male patients=58) elected to undergo genetic testing, ranging from single-gene testing to panel testing. The most common form of testing in this cohort was panel testing encompassing 83.4% of those tested (n=560) followed by BRCA1 and 2 testing (n=66 [9.8%]) and single-gene testing (n=45 [6.7%]). The schematic of testing described is depicted in Figure 1. Additionally, a breakdown of the various panel tests ordered on that cohort of patients is depicted in Table 1. Of note, panel testing, as a percentage of total testing, became more common over the duration of the study (2015: 76%; 2016: 90%; χ2 statistic 22.3, P<.01).
Of 670 at-risk patients who underwent any genetic testing, 17.3% (n=116; male patients=16) were found to have a deleterious or likely pathogenic mutation. Of those who underwent BRCA-limited testing, 26 (3.9% of the full testing cohort) had abnormal results. Of those who underwent panel testing, abnormal results were found in 65 participants (9.7% of the full testing cohort). For these 65 patients, non-BRCA mutations (predominantly CHEK2) were found in 49 (75%), or 7.3% (49/670) of the testing population. Of those who underwent single-gene testing, 25 (3.7% of the full testing cohort) were found to have abnormal results.
The distribution of deleterious mutations found and their associated cancer risks are depicted in Table 2. Among the 65 patients who underwent panel testing, 69 deleterious mutations were found (four of the patients were found to have two mutations), which is illustrated in Figure 2. Only one fourth (26% [n=17]) of the positive, panel-tested individuals were found to have BRCA mutations, and one of those patients was found to have both a BRCA and a non-BRCA mutation. Three fourths (75% [n=49]) of positive, panel-tested individuals were diagnosed with non-BRCA mutations that would have been missed by BRCA or targeted testing alone. This group represents 42% (n=49/116) of those who had any positive genetic test.
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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