Abstract
It is estimated that 5% to 10% of all cancers are related to a hereditary cancer syndrome. However, specific cancers, such as pancreatic and ovarian cancers, are related to hereditary cancer syndromes 15% to 20% of the time. Genetic testing guidelines for hereditary cancer syndromes are frequently reviewed and updated by the National Comprehensive Cancer Network (NCCN). The purpose of this retrospective analysis is to identify carriers of pathogenic variants or hereditary cancer syndrome who do not meet NCCN criteria for testing and compare the results with previous studies. The data obtained can be used to provide recommendations to assess current guidelines for testing and evaluate the benefit of comprehensive panel testing vs. standard testing for specific hereditary cancer syndromes. This project is a retrospective review of clinical histories of patients who had multigene panel testing between September 2015 and February 2019 through a cancer outreach and risk assessment (CORA) program. Frequencies analyses were performed to analyze results. A total of 233 individuals were included in the analysis: 171 met BRCA1/2 testing criteria, 66 met Lynch syndrome criteria, and 4 met polyposis criteria. Of the individuals meeting established criteria for testing, 39 were identified with pathogenic variants. However, only 10 of these individuals were identified with a pathogenic variant associated with the criteria for which they met. Genetic testing that is limited to only those patients with genes associated with hereditary cancer syndromes may lead to exclusion of other potentially actionable genes, which may impair a patient's ability to receive additional screening or preventative measures.
Approximately 5% to 10% of all cancers can be related to germline pathogenic variants (Marta et al., 2019), although that number is expected to climb as more information on the genetic origin of cancers becomes available. At this time, up to 24% of ovarian cancers (Ring et al., 2017), 10% of pancreatic cancers (Ohmoto et al., 2019), and 5% to 10% of breast cancers are hereditary (Göhler et al., 2017). The most commonly recognized germline pathogenic variants that increase one's risk for the development of cancer are BRCA1/2 and Lynch-related genes (MLH1, MSH2, MSH6, PMS2, and EPCAM). However, more genes are being identified that increase one's risk for cancer development, and it is important to ensure that practitioners are utilizing the most up-to-date information when ordering testing. A critical mutation could easily be missed if testing is limited to only those genes in a basic genetic panel or those that a practitioner is familiar with (LaDuca et al., 2014).
BRCA testing was introduced in 1995 to evaluate patients for hereditary breast and ovarian cancer (HBOC) syndrome. Potential patients for testing included individuals diagnosed with a high-risk breast cancer or with strong family histories of breast cancer. A high-risk breast cancer is considered a diagnosis at or below the age of 45, triple-negative breast cancer under the age of 60, or multiple family members with a breast cancer diagnosis (Sankar et al., 2006). It was not until 2013 when the Supreme Court of the United States ruled that a gene could not be patented (Myriad Genetics held a previously acquired patent on BRCA1/2 testing [“Association for Molecular Pathology v. Myriad Genetics, Inc,” 2012]) that other labs were able to begin testing for pathogenic variants in BRCA, and panel testing came to the forefront of oncology care. Since then, multigene panel testing continues to grow, and practitioners' perceptions of appropriate testing is evolving (Hooker et al., 2017). Unfortunately, due to a lack of genetics knowledge and management guidelines for practitioners across the country, many individuals are undergoing limited genetic testing (Douma et al., 2016). This project will investigate the appropriateness of limited testing vs. comprehensive panel testing in individuals who meet criteria set by the National Comprehensive Cancer Network (NCCN).
LITERATURE REVIEW
Genetic testing for hereditary cancer syndromes allows for patients to identify potential lifetime risk factors for the development of a variety of cancers. Additionally, it allows practitioners to modify screenings and interventions to better serve the patient through early identification or cancer prevention. With the availability of multigene panel testing, more options are accessible to both practitioners and patients (Robson et al., 2015).
Current guidelines from the NCCN (2019) restrict recommendations for genetic testing to a few genes: BRCA1/2, PTEN, TP53, MSH6, MSH2, MLH1, EPCAM, PMS2, and MUTYH. In addition, the criteria for testing is significantly limited, requiring specific criteria for individuals to meet the standards dictated. However, research, as well as current practices, are beginning to show the importance of expanded testing outside of NCCN Guidelines, as actionable pathogenic variants are being identified in unexpected patients (Espenschied et al., 2017). Actionable pathogenic variants are defined as any pathogenic mutation that currently has a recommendation for alterations to management or screening options (Carr et al., 2016).
In 2019, The American Society of Breast Surgeons (ASBS) published their consensus guidelines on genetic testing for hereditary breast cancer. The consensus outlines the recommendation for genetic testing in all individuals with a personal history of breast cancer, regardless of age at diagnosis, family history, and hormone receptor status. Additionally, patients who previously underwent genetic testing for pathogenic variants only in BRCA1 and BRCA2 should be considered for updated or additional testing. Beitsch and colleagues (2019) outline the importance of testing patients outside of the guidelines due to the age restrictions. A patient diagnosed with triple-negative breast cancer at the age of 60 qualifies, but if the patient were diagnosed one day after their 61st birthday, they would not be recommended for testing.
A poster presentation at the 2019 San Antonio Breast Cancer Symposium further illustrated the importance of expanded testing through the retrospective review of 2,806 individuals. Within this cohort, 11.9% had an identified germline pathogenic mutation, only half of which were BRCA1 or BRCA2 (Hoste et al., 2019).
Evidence supporting comprehensive testing in cancers other than breast cancer is prevalent, too. In a cross-sectional study of 3,607 men with a personal history of prostate cancer, 620 (17.2%) were found to have pathogenic germline pathogenic variants. 229 (37%) of these individuals did not meet NCCN criteria for testing (Nicolosi et al., 2019).
Testing for Lynch syndrome is also restricted by the Bethesda and Amsterdam guidelines (NCCN, 2019). However, studies suggest that due to the Guideline's limitations, Lynch syndrome is often undiagnosed. Approximately 3% to 5% of colon cancers are associated with Lynch syndrome. Of women who are later found to have a Lynch-related cancer, 50% of these are diagnosed with a gynecological cancer as the first primary (Kirkpatrick & Cotton, 2018).
Pritzlaff and colleagues (2017) performed a retrospective study of 715 male breast cancer patients who underwent multigene panel testing from March 2012 through June 2016. Per NCCN Guidelines, the presence of a male breast cancer is an immediate indication for germline testing for HBOC syndrome, although it is limited to BRCA1 and BRCA2. Of these patients, 18.1% tested for a pathogenic mutation, with the most frequently identified pathogenic variants found in BRCA2 and CHEK2. Additional variants were found in PALB2. These variants indicated an increased risk for male breast cancer in BRCA2, CHEK2, and PALB2. Additionally, pathogenic variants were also identified in ATM, BARD1, NF1, RAD51D, NBN, and MRE11A, although they were not as significant as the previously mentioned variants.
Churpek and colleagues (2015) performed an evaluation of 289 African American females with a personal history of invasive breast cancer in addition to other high-risk characteristics, such as tumor characteristics or family history. Recent studies found that breast cancers diagnosed in an African American female have a higher likelihood of being triple negative than in white or Hispanic women (Dietze et al., 2015). At this time, it is not known whether the difference in hormone receptor status is related to disparities or biology. Triple-negative breast cancer is more aggressive and an automatic indication for genetic testing if diagnosed at 60 years old or older (NCCN, 2019).
Based on the study by Dietze and colleagues (2015), it cannot adequately be attributed to the general population of African American women. However, the information is still valid, as a study was performed by utilizing a multigene panel test. 68 of the 289 subjects were identified to carry a pathogenic genetic variation, accounting for 23.5%, which is higher than the expected 5% to 10% within the general population. Of those identified with pathogenic variants, BRCA1 and BRCA2 were the most prevalent at 80%, while the other 20% consisted of pathogenic variations in PALB2, CHEK2, BARD1, ATM, PTEN, and TP53.
In a systematic review of eight different studies, Prapa and colleagues (2017) provided an intensive overview of the presence of additional pathogenic variants, outside of BRCA1 and BRCA2, by investigating the results of 7,272 subjects with either breast or ovarian cancer. Additional genes identified through this study related to breast cancer susceptibility are CDH1, PTEN, STK11, TP53, ATM, CHEK2, NF1, PALB2, BRIP1, NBN, RAD51C, and RAD51D.
As depicted throughout retrospective studies, there are several genes being identified in patients meeting NCCN Guidelines for specific pathogenic variants, as well as in patients who do not meet current guidelines. Many of these pathogenic variants are considered actionable, and their presence may affect an individual's treatment. Therefore, consideration should be given for all patients undergoing genetic testing to have comprehensive panel testing performed instead of limited germline testing (Hoste et al., 2019; Nicolosi et al., 2019; Prapa et al., 2017).
PURPOSE
The purpose of this project is to assess the benefit of utilizing multigene panel testing over disease-specific testing for patients meeting NCCN Guidelines for HBOC syndromes, Lynch syndromes, and polyposis syndromes, and determine if NCCN Guidelines should be changed to include panel testing and be a resource to influence coverage by insurance companies.
This project attempts to answer the following questions: How many actionable genes were identified outside of the expected genetic pathogenic variants in patients meeting NCCN criteria for testing? How many patients who didn't meet NCCN Guidelines were identified to carry an actionable mutation? How many patients tested positive for a pathogenic mutation outside of what was expected, such as Lynch syndrome when HBOC is suspected? Of all patients meeting NCCN criteria for testing, how many were identified with a pathogenic mutation?
METHODS
Study Population
Deidentified molecular results of patients seen within a community cancer outreach and risk assessment (CORA) program from September 1, 2015, through February 29, 2019, were evaluated. All patients had clinical histories reviewed for personal and family history of malignancy or other qualifying criteria per NCCN Guidelines. Patients under the age of 18 and older than the age of 88 were excluded from the study. Any patients whose testing was ordered by a different practitioner at an outside facility were not included. Pregnant patients were not included in the study.
Demographics
Demographics and clinical characteristics of the studied cohort are shown in Table 1. A total of 233 subjects were analyzed to see if they met NCCN criteria. Results of testing utilizing a 67-gene panel are shown. Patients were predominantly female (90%), and the mean age at testing was 51 years. A number of patients (73%) met NCCN criteria for BRCA1/2 testing, while NCCN criteria for Lynch syndrome patients was met by 28%. Additional NCCN criteria evaluated include Li-Fraumeni syndrome (4%), Cowden syndrome (0%), Peutz-Jeghers (0%), polyposis (2%), and single-site or specific site analysis of previous identified gene within family (7%). Some patients met NCCN criteria for two or more syndromes (29%), while 40 (17%) patients met criteria for both BRCA1/2 and Lynch. Of those tested, 14% did not meet any of the criteria set by the NCCN.
Table 1. Patient Demographics and Clinical Characteristics.
| N | % | |
|---|---|---|
| Female | 210 | 90.1 |
| Male | 23 | 9.9 |
| Age at testing, mean (range) | 51 (22–87) | |
| Testing criteria met | ||
| BRCA1/2 | 171 | 73.3 |
| Lynch | 66 | 28.3 |
| Li-Fraumeni | 9 | 3.9 |
| Cowden | 0 | 0.0 |
| Peutz-Jeghers | 0 | 0.0 |
| Polyposis | 4 | 1.7 |
| Single-site | 16 | 6.9 |
| BRCA1/2 and Lynch | 40 | 17.2 |
| NCCN criteria not met | 33 | 14.2 |
Both the clinical facility and university institutional review boards reviewed this research for exempt status. The database was maintained on an encrypted computer connected to an encrypted network and through a hospital network's technologies system. Within the database, no identifiable patient information was maintained. The database only included a study ID number, sex, age range, and testing results. The study identification number was linked to the original database maintained by the CORA program, which is password protected and only accessible by the program's manager/practitioner and the program's coordinator.
Data Collection
The database was created for the purpose of maintaining numbers of patients tested, number of positive, negative, and variant of uncertain significance results, and type of testing utilized. For this project, each patient was randomly assigned a study number and moved to a separate, password-protected spreadsheet. Within the database created for this project, only the study number, age of patient at time of testing, gender, results of testing (positive, negative, or variant of uncertain significance) and genes identified, if any, were recorded. A variant of uncertain significance is an inconclusive result. It indicates a mutation in one's gene—not the same mutation that is proven to be an increased risk of cancer, but a mutation separate from the expected DNA make-up (Greenblatt, 2015). Due to variations in panel sizes and genes tested, only those patients who underwent comprehensive testing through Ambry Genetics with the CancerNext-Expanded panel, analyzing 67 genes, were included.
All selected participants were retrospectively analyzed for NCCN criteria met or not met. The criteria utilized were the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 3.2019, published on January 18, 2019, and the NCCN Guidelines for High-Risk Assessment: Colorectal, Version 1.2018, published on July 12, 2018. Patients were assessed for meeting the criteria for the following pathogenic variants/syndromes: HBOC (BRCA1/2), Li-Fraumeni syndrome (TP53), Cowden syndrome (PTEN), Peutz-Jeghers (STK11), Lynch syndrome (MSH2, MSH6, MLH1, EPCAM, PMS2), and polyposis syndromes (APC, MUTYH).
Data were downloaded to an Excel spreadsheet for data analysis. Frequencies procedures were performed for data analyses. The following comparisons were made:
Patients positive for a pathogenic mutation meeting NCCN Guidelines vs. patients positive for a pathogenic mutation not meeting NCCN criteria.
Patients who meet NCCN Guidelines and test positive vs. negative vs. inconclusive
Patients positive for pathogenic mutation within the expected syndrome (e.g., HBOC, Lynch, etc.) vs. positive patients outside of expected syndrome.
RESULTS
Results of genetic testing were classified as negative, positive (pathogenic or likely pathogenic variant identified), and variant of uncertain significance. In comparison to the expected 5% to 10% findings of pathogenic variants, pathogenic or likely pathogenic variants were identified in 15.9% of patients, 44.2% negative for pathogenic variants, and 39.9% inconclusive.
BRCA1/2 Criteria Met
Patients meeting testing criteria for BRCA1/2 accounted for 171 (73.3%) patients. Of these, 22 (12.9%) identified with pathogenic variants (Table 2), 78 (45.6%) tested negative, and 71 (41.5%) were classified as variant of uncertain significance. Only two of those individuals testing positive were found to have a pathogenic variant in BRCA2. All other individuals testing positive were found to have pathogenic variants outside of the expected BRCA1 and BRCA2 genes (specifically SDHA, MSH6, CHEK2, MSH2, NF1, RAD51C, RET, HOXB13, FH, BMPR1A, MUTYH, CDKN2A, POT1, ATM, TMEM127, and RAD50; see Table 2). One patient was identified to carry two pathogenic variants, HOXB13 and RET, while another identified with pathogenic variants in CHEK2 and MUTYH. Seven of these unexpected identified pathogenic variants are currently considered actionable by the NCCN.
Table 2. BRCA1/2 Criteria Met, Pathogenic Variants.
| Gene | Total PV, n | % of PVs |
|---|---|---|
| BRCA a | 2 | 9.1 |
| SDHA a | 1 | 4.5 |
| HOXB13 | 2 | 9.1 |
| MUTYH | 3 | 13.6 |
| MSH6 a | 2 | 9.1 |
| CHEK2 a | 2 | 9.1 |
| MSH2 a | 1 | 4.5 |
| POT1 | 1 | 4.5 |
| RAD51C a | 1 | 4.5 |
| RET | 1 | 4.5 |
| FH | 1 | 4.5 |
| BMPR1A | 1 | 4.5 |
| CDKN2A | 1 | 4.5 |
| ATM a | 1 | 4.5 |
| TMEM127 | 1 | 4.5 |
| RAD50 | 1 | 4.5 |
Note. One patient identified with both MUTYH and CHEK2 pathogenic variants, and one patient identified with RET and HOXB13 pathogenic mutations.
PV = pathogenic variant.
Considered actionable per NCCN Guidelines.
Lynch Syndrome Criteria Met
Sixty-six (28.3%) of patients met Lynch syndrome testing. Negative results were classified in 28 (42.4%), variant of uncertain significance in 22 (33.3%), and positive or pathogenic variants in 16 (24.2%) patients, accounting for 18 total pathogenic variants (Table 3). Lynch-related variants were identified in seven of those individuals testing positive, four with MSH6, two with MSH2, and one with EPCAM. The patient testing positive for EPCAM also tested positive for a pathogenic variant in CHEK2. No pathogenic variants were identified in MLH1 or PMS2 for those meeting Lynch syndrome criteria. Actionable pathogenic variants outside of the Lynch syndrome spectrum were identified in five patients, CHEK2 in three patients, BRCA1 in one patient, and CDH1 in one patient. Additional pathogenic variants identified included HOXB13, BLM, CDKN2A, RET, and MUTYH.
Table 3. Lynch Syndrome Criteria Met, Pathogenic Variants.
| Gene | Total PV, n | % of PVs |
|---|---|---|
| BLM | 1 | 5.6 |
| BRCA1 a | 1 | 5.6 |
| CDH1 a | 1 | 5.6 |
| CDKN2A | 1 | 5.6 |
| CHEK2 a | 3 | 16.7 |
| EPCAM a | 1 | 5.6 |
| HOXB13 | 2 | 11.1 |
| MSH2 a | 2 | 11.1 |
| MSH6 a | 4 | 22.2 |
| MUTYH | 1 | 5.6 |
| RET | 1 | 5.6 |
PV = pathogenic variant.
Note. One patient identified with RET and HOXB1 pathogenic mutations, and one patient identified with CHEK2 and EPCAM pathogenic mutations.
Considered actionable per NCCN Guidelines.
Both BRCA1/2 and Lynch Syndrome Criteria Met
Of the patients meeting both BRCA1/2 and Lynch testing criteria (40), 17.5% were found to have pathogenic variants, 47.5% were negative, and 35% had inconclusive results. Of the pathogenic variants identified, only three (7.5%) were in the expected genes associated with BRCA1/2 and Lynch syndrome, all three being Lynch related. One individual with a pathogenic variant of CHEK2 was identified, which is associated with modified screening and management per NCCN Guidelines. The remaining pathogenic variants were considered nonactionable at this time by the NCCN (2019).
None of the individuals meeting Li-Fraumeni syndrome testing criteria (n = 9) were found to have a pathogenic variant in TP53, which is associated with the diagnosis of Li-Fraumeni. Of those tested, two (22%) tested negative, five (55.6%) identified to have a variant of uncertain significance, and two (22.2%) identified with pathogenic variants. One was a heterozygous for a pathogenic mutation in MUTYH. The other was identified with two pathogenic variants, one in CHEK2 and one in MUTYH. A heterozygous mutation in MUTYH was nonactionable at the time.
Four (1.7%) patients met polyposis syndrome testing criteria. Two (50%) identified with variant of uncertain significance, one (25%) tested negative, and one (25%) tested positive for a pathogenic variant in APC, which is associated with the expected polyposis syndrome.
Those not meeting any NCCN criteria accounted for 33 (14.2%) of patients. Of those evaluated, three (9.1%) identified with pathogenic variants, two of which were considered actionable (CHEK2 and PALB2). The other individual was found to have a pathogenic variant in CDKN2A, which is associated with a hereditary pancreaticmelanoma cancer syndrome. Fifteen (45.5%) tested negative and fifteen (45.5%) identified with variant of uncertain significance. Pathogenic and likely pathogenic variants are depicted in Table 4.
Table 4. BRCA1/2 and Lynch Syndrome Criteria Met, Pathogenic Variants.
| Gene | Total PV, n | % of PVs |
|---|---|---|
| APC | 1 | 2.5 |
| ATM | 1 | 2.5 |
| BLM | 1 | 2.5 |
| BMPR1A | 1 | 2.5 |
| BRCA1 | 1 | 2.5 |
| BRCA2 | 2 | 5.0 |
| BRIP1 | 1 | 2.5 |
| CDH1 | 1 | 2.5 |
| CDKN2A | 3 | 7.5 |
| CHEK | 5 | 12.5 |
| EPCAM | 1 | 2.5 |
| FH | 1 | 2.5 |
| HOXB13 | 2 | 5.0 |
| MSH2 | 2 | 5.0 |
| MSH6 | 5 | 12.5 |
| MUTYH | 3 | 7.5 |
| NF1 | 1 | 2.5 |
| PALB2 | 1 | 2.5 |
| POT1 | 2 | 5.0 |
| RAD50 | 1 | 2.5 |
| RAD51C | 1 | 2.5 |
| RET | 1 | 2.5 |
| SDHA | 1 | 2.5 |
| TMEM127 | 1 | 2.5 |
| Total | 40 |
Note. PV = pathogenic variant. Only genes identified with a pathogenic variant included in Table 2.
DISCUSSION
Within the sample population, 15.9% of patients tested were identified to carry pathogenic variants. Of the 53 patients meeting either BRCA1/2, Lynch syndrome, Li-Fraumeni syndrome, or polyposis syndrome criteria, only 10 (18.9%) of the positive results were consistent with the syndromes and associated genes. Therefore, if the ordering practitioner had limited testing related to only specific genes associated with criteria, over 80% of pathogenic variants would have been missed. Although not all of the identified variants are considered actionable, they may become actionable in the future. NCCN Guidelines are updated on a regular basis with expert panelists working together to update screening guidelines, including adding genes to actionable pathogenic variants.
Additionally, three patients who did not meet NCCN criteria were identified as having pathogenic variants. By limiting genetic testing to only those meeting criteria, the overall population may be missing potential risk factors. While population testing may not be indicated, expanding guidelines for testing should include individuals with all breast cancer diagnoses or strong family histories of malignancy, regardless of cancer type. All of the groups identified, excluding polyposis, surpassed the 5% to 10% estimated presence of pathogenic variants, indicating the rate of pathogenic variants in the study group was higher than expected.
Limitations
Significant limitations exist within this analysis due to the small sample size. Additionally, all patients were within the same geographic area and tested through the same community program. A larger study evaluating criteria met and genes identified that utilizes a larger population size with diverse patients from all racial, social, and ethnic backgrounds should be considered.
Clinical Implications
Implications for clinical impact are based on the results of this analysis, as well as previously cited articles. Although many of the genes analyzed in the 67-gene panel are currently not actionable per NCCN Guidelines, there are still a number that are outside the spectrum of testing but may influence screening and management. For instance, while CHEK2, ATM, and PALB2 are less penetrant than BRCA1 and BRCA2, they are considered moderate risk and increased screening may be considered (Acevedo et al., 2018).
Advancements in cancer treatment are also influencing the need for genetic testing. With the introduction of poly(ADP-ribose) polymerase (PARP) inhibitors and the U.S. Food & Drug Administration's approval for use in prostate and ovarian cancer patients with BRCA pathogenic variants, genetic testing may directly influence treatment (Buchtel et al., 2018). In early stage prostate cancer patients, treatment will not immediately be affected by a BRCA mutation; however, delay in testing can result in a delay in treatment in the event of recurrence or metastasis (Giri et al., 2019).
Additional recommendations include:
All individuals, regardless of personal cancer history, should be evaluated by primary care physicians on an annual basis for cancer risk and risk of genetic pathogenic variants that increase the risk for cancer. The annual review is imperative due to the potential for new cancer diagnoses within the family.
Individuals tested prior to 2013 should consider additional, expanded panel testing, as a mutation may be present that was not previously tested for.
Expansion of NCCN criteria to promote panel testing instead of limited syndrome only–related pathogenic variants.
Education of primary care providers, oncologists, and advanced practitioners on assessments, what to look for, and appropriate testing.
CONCLUSION
Further studies are indicated to evaluate patients meeting criteria compared with those who do not, as well as pathogenic variants identified outside of the expected spectrum. Additionally, concern should be given to the mental distress that genetic testing may put on an individual, especially when little to no information is available on newer or nonactionable genes (Harris & Hutson, 2019). Testing decisions should be individualized based on personal history, family history, and psychological mentality. Expanded panel testing may not be appropriate if a patient has a high level of anxiety and a variant of uncertain significance result. However, it is the responsibility of the practitioner to offer all options to the patient, providing the opportunity for a well-informed decision-making process.
Footnotes
The authors have no conflicts of interest to disclose.
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