National Comprehensive Cancer Network Testing Research Articles

Germline genetic mutations in a multi-center cohort of 248 phyllodes tumors.

Germline genetic mutations in women with phyllodes tumors (PT) are understudied, although some describe associations of PT with various mutations. We sought to determine the prevalence of pathogenic/likely pathogenic (P/LP) variants in women with PT. A 6-site multi-center study of women with a PT was initiated, then expanded nationally through an online "Phyllodes Support Group." All women underwent 84-gene panel testing. We defined eligibility for testing based on select NCCN (National Comprehensive Cancer Network) criteria (v1.2022). Logistic regression was used to estimate the association of covariates with the likelihood of a P/LP variant. 274 women were enrolled: 164 (59.9%) through multi-center recruitment and 110 (40.1%) via online recruitment. 248 women completed testing; overall 14.1% (N = 35) had a P/LP variant, and over half (N = 19) of these individuals had a mutation in genes associated with autosomal dominant (AD) cancer conditions. The most common AD genes with a P/LP variant included CHEK2, ATM, and RAD51D. A quarter of participants (23.8%) met NCCN criteria for testing, but we found no difference in prevalence of a P/LP variant based on eligibility (p = 0.54). After adjustment, the presence of P/LP variants was not associated with age, NCCN testing eligibility, or PT type (all p > 0.05). Our study demonstrates that 7.7% of women with PT harbor germline P/LP variants in genes associated with AD cancer conditions. Early identification of these variants has implications for screening, risk reduction, and/or treatment. National guidelines for women with PT do not currently address germline genetic testing, which could be considered.

A targeted panel of actionable high-risk hereditary cancer predisposition genes to identify patients with pathogenic/likely pathogenic variants (PVs) irrespective of meeting established NCCN testing criteria.

10596 Background: Current germline cancer testing guidelines are limited to patients who meet specific personal and family cancer history (PH, FH) criteria. Our objective was to determine if differences in PV rates exist based on meeting National Comprehensive Cancer Network (NCCN) testing criteria in patients who underwent testing for known actionable genes. Methods: 29 genes with actionable NCCN management guidelines were evaluated. Consecutive patients (N=195,615) aged 18 to 100 years had hereditary cancer testing at a commercial laboratory at the ordering clinician’s discretion that included at least the 29 genes between June 2020 and August 2023. Per clinician-reported patient features (e.g. FH, PH, age), patients were categorized as meeting or not meeting current NCCN testing criteria for breast/ovarian/pancreatic (BOP v2.2024), and colorectal cancer (v1.2023). PV rates were calculated for all genes associated with breast, endometrial, ovarian, prostate, pancreatic, and colorectal cancer risk. Results: PVs were reported in 6634/105,194 (6.3%) patients that met the testing criteria and 5134/90,421 (5.7%) that did not. Of patients with a PV, 5134/11,768 (43.6%) did not meet NCCN testing criteria. When comparing patients with PVs based on NCCN testing criteria, patients were similar in age (median [Q1, Q3], 43.6 [35.0, 56.1] v 42.5 [34.7, 56.6] years) and sex (female 91.5% v 91.3%). While PH and FH were comparable, a PH of cancer (31.5% v 36.1%, OR=0.81, 95% CI 0.75-0.88, p<0.001) and/or a FH of cancer (83.9% v 97.1%, OR=0.16, 95% CI [0.13-0.18], p<0.001) were slightly lower in patients who did not meet criteria compared to those who met testing criteria. On evaluating results in genes associated with individual cancer types, similar PV rates between the groups were observed (Table). Among all patients with PVs, the most common genes were CHEK2, BRCA1, BRCA2, and ATM. Most patients had only 1 PV reported (met: 96.5%, not met: 97.5%). Conclusions: In this cohort of patients who underwent germline testing, approximately 40% of patients with PVs in this study did not meet existing NCCN testing criteria. PV rates were similar between patients that met criteria and those that did not. Broadening existing testing criteria may reduce the number of patients who would otherwise be missed, thereby allowing for treatment decision-making and cascade testing of family members. [Table: see text]

Perioperative genetic testing and time to surgery in patients with breast cancer

BackgroundTime to treatment has been identified as a quality metric, with longer time to treatment associated with poorer outcomes. Genetic evaluation is an integral part of treatment counseling for patients with breast cancer. With expanding indications for genetic testing and consideration of expansion of genetic testing to all patients with a personal history of breast cancer, this study aims to evaluate the effect of genetic evaluation on the time interval from initial surgical visit to surgery. MethodsA retrospective review of patients undergoing upfront surgery for stage 0–3 breast cancer from June 2022 to December 2022. Patient demographics, treatment characteristics, National Comprehensive Cancer Network criteria for genetic testing, and results were obtained. ResultsThe study included 492 patients (489 females). Eighty-one (16.2%) were ≤50 years of age at diagnosis. In total, 281 patients (57.1%) met National Comprehensive Cancer Network criteria for genetic testing and 199 consulted with a genetic counselor (72.4%). Seventy-six patients (27.6%) not meeting National Comprehensive Cancer Network criteria pursued genetic counseling. In total, 218 patients (79.3%) referred for genetic counseling completed testing. Mean turnaround time to genetic testing result was 11 days (range, 6-66 days). Twenty-six patients (11.9%) had a pathogenic or likely pathogenic variant. Twenty-four of these patients met National Comprehensive Cancer Network testing criteria (92.3%) and 2 did not (7.7%). The time to treatment for patients undergoing genetic testing was 33 vs 34 days in those without testing (P = .45). Three patients (11.5%) with pathogenic or likely pathogenic variants altered their initial surgical plan due to their genetic testing results. Seven patients with pathogenic or likely pathogenic variant results returning postoperatively did not undergo additional surgery. ConclusionHereditary breast cancer evaluation and genetic testing did not appear to delay time to treatment for patients with breast cancer in our study cohort.

Effect on Germline Mutation Rate in a High-Risk Chinese Breast Cancer Cohort after Compliance with The National Comprehensive Cancer Network (NCCN) 2023 v.1 Testing Criteria.

The National Comprehensive Cancer Network (NCCN) testing criteria for the high-penetrance breast cancer susceptibility genes, specifically BRCA1, BRCA2, CDH1, PALB2, PTEN, and TP53, have been recently modified in 2023 to 2023 v.1. The following criteria have been changed: (1) from a person diagnosed with breast cancer at ≤45 to ≤50; (2) from aged 45-50 of personal breast diagnosis to any age of diagnosis with multiple breast cancers; and (3) from aged ≥51 of personal breast diagnosis to any age of diagnosis with family history listed in NCCN 2022 v.2. High-risk breast cancer patients (n = 3797) were recruited from the Hong Kong Hereditary Breast Cancer Family Registry between 2007 and 2022. Patients were grouped according to NCCN testing criteria 2023 v.1 and 2022 v.2. A 30-gene panel for hereditary breast cancer was performed. The mutation rates on high-penetrance breast cancer susceptibility genes were compared. About 91.2% of the patients met the 2022 v.2 criteria, while 97.5% of the patients met the 2023 v.1 criteria. An extra 6.4% of the patients were included after the revision of the criteria, and 2.5% of the patients did not meet both testing criteria. The germline BRCA1/2 mutation rates for patients meeting the 2022 v.2 and 2023 v.1 criteria were 10.1% and 9.6%, respectively. The germline mutation rates of all 6 high-penetrance genes in these two groups were 12.2% and 11.6%, respectively. Among the additional 242 patients who were included using the new selection criteria, the mutation rates were 2.1% and 2.5% for BRCA1/2 and all 6 high-penetrance genes, respectively. Patients who did not meet both testing criteria were those with multiple personal cancers, a strong family history of cancers not listed in the NCCN, unclear pathology information, or the patient's voluntary intention to be tested. The mutation rates of BRCA1/2 and the 6 high-penetrance genes in these patients were 5.3% and 6.4%, respectively. This study provided a real-world application of the revision of NCCN guidelines and its effect on the germline mutation rate in the Chinese population. Applying the updated criteria for further genetic investigation would increase the positive detection rate, and potentially more patients would benefit. The balance between the resource and outcome requires careful consideration.

Implementation of universal, pan-cancer germline genetic testing in patients with cancer in Jordan.

10580 Background: Detection of pathogenic germline variants (PGVs) has a significant and growing impact on the management of patients with many types of cancer. Most research to date evaluated individuals of European background, which can result in skewed genetic testing criteria and variant interpretation. Additional data are needed from diverse populations. This study aimed to investigate a universal germline testing strategy and the pattern and frequency of PGVs among all newly diagnosed cancer patients at a single center in Jordan. Methods: In this prospective, observational study, consecutive patients newly diagnosed with cancer were classified as meeting or not meeting National Comprehensive Cancer Network (NCCN) germline genetic testing criteria. All patients underwent an 84-gene panel test, independent of age, stage or family history. Demographics and clinical history were collected and analyzed from information provided by the clinicians on the test requisition form. Descriptive statistics were employed, and statistical significance was determined by two-tailed Fisher’s exact test and unpaired t test. Results: In total, 1377 cancer patients of Arabic background were enrolled, of which 831 (60.3%) met NCCN criteria (Table). PGVs were identified in 210 (15.3%). Excluding the 29 patients who were carriers for autosomal recessive conditions, 192 PGVs were identified in 181 (13.1%) patients. PGVs were most commonly identified in APC (p.I1307K variant, 55, 28.6%), BRCA2 (35, 18.2%), BRCA1 (21, 10.9%), and TP53 (12, 6.3%). While patients who met NCCN testing criteria were more likely to have a PGV (p<0.0001), 44 (24.30%) patients with PGVs did not meet criteria. Among those with PGVs, 177 (97.8%) were potentially eligible for increased screening per NCCN/expert opinion guidelines, 69 (38.1%) targeted therapies, and 89 (49.2%) clinical trials; this included 41 (22.7%), 6 (3.3%), and 14 (7.7%) patients, respectively, that did not meet NCCN testing criteria. 1445 variants of uncertain significance (VUS) were identified in 833 (57.7%) patients, but no difference in VUS rate was observed between those meeting and not meeting criteria (p=0.7354). Conclusions: Overall PGV rate among cancer patients from one center in Jordan was similar to that reported in the literature. While the VUS rate was high, similar rates were observed in those meeting and not meeting criteria. Testing restricted to guidelines could have missed approximately a quarter of patients with PGVs, >95% of whom might qualify for increased screening, targeted therapies, and/or clinical trials. [Table: see text]

Clinical Germline Testing Results of Men With Prostate Cancer: Patient-Level Factors and Implications of NCCN Guideline Expansion.

Men with PC underwent multigene germline genetic testing for PVs from June 2016 to December 2018, and trends were compared. The association of patient-level factors with a PV germline testing result, where ≥ 1 PV was identified, was assessed using analysis of variance and univariate logistic regression. Sensitivity analyses were limited to clinically actionable variants and those associated with disease severity or progression (BRCA1/2 and ATM). Of 408 men undergoing germline testing, 42 (10.3%) men had PVs and 366 (89.7%) men did not have PVs identified. The proportion of men identified with a germline PV remained stable following testing criteria expansion (9.4% v 10.6%, P = .73). No patient-level factors were significantly associated with increased odds of a PV germline testing result, including age at diagnosis, race, pretreatment prostate-specific antigen, Gleason grade group, NCCN risk group, and family history of cancer (breast and/or ovarian, prostate, or any cancer). This study demonstrated a stable PV detection rate in men with PC using expanded criteria aligned to the updated NCCN testing guidelines. However, we did not find strong evidence to suggest that patient-level factors are associated with PV germline testing results. These findings support the recent expansion of NCCN germline testing guidelines in PC.

Abstract P6-08-01: Comparison of recommendations for germline genetic testing in an unselected cohort of patients with breast cancer

Abstract Purpose: To determine the sensitivity of germline hereditary cancer genetic testing recommendations for detection of pathogenic mutations in breast cancer predisposition genes in an unselected cohort of breast cancer patients. Patients and Methods: The study population included patients enrolled in a prospective breast cancer registry after being seen at Mayo Clinic for newly diagnosed breast cancer between 2004 and 2016. All patients were subjected to germline mutation testing for 12 known breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C, RAD51D and TP53). Results from testing of all breast cancer patients according to American Society of Breast Surgeons (ASBrS) genetic testing recommendations and patients meeting National Comprehensive Cancer Network (NCCN) criteria for BRCA1/2 testing, based on age at diagnosis and personal and family history of cancer, were compared. Results: Among the 4516 patients in the cohort, the median age at diagnosis of breast cancer was 57 years, 80.5% had estrogen receptor positive tumors, and 43% had a family history of breast cancer. All patients in the cohort met ASBrS criteria for hereditary cancergenetic testing, 2050 (45.4%) met NCCN criteria, 1892 (41.9%) did not meet NCCN criteria, and 574 (12.7%) patients could not be fully evaluated for NCCN testing criteria due to missing data. The frequencies of pathogenic variants in the cohort are shown in Table 1. Patients meeting NCCN criteria were more likely to carry a pathogenic variant compared to those who did not (9.8% vs. 3.8%, p<0.001, Table 1). However, 72 (26.5%) out of the 272 patients with mutations in 12 breast cancer predisposition genes and 15 (12.4%) out of 121 with mutations in BRCA1/2 were overlooked when NCCN selection criteria alone were applied. When testing was expanded to include all patients with breast cancer diagnosed at age ≤65 and/or meeting NCCN testing criteria, only 20 (7.4%) out of 272 mutation carriers in 12 breast cancer genes and 2 (1.6%) out of 121 BRCA1/2 mutation carriers were overlooked. However, this increased the number tested to detect one mutation carrier on average from 17 to 25 for BRCA1/2 and from 9 to 12 for the 12 breast cancer predisposition genes. In total, this age cutoff led to an increase in the number of patients tested by 28% while the number of patients in the cohort that need not undergo germline genetic testing was 20%. Conclusions: Although NCCN criteria for BRCA1/2 germline genetic testing detect the majority of predisposition gene mutation carriers, a significant number of carriers are missed in an unselected cohort of breast cancer patients using these criteria. Expanding the current NCCN criteria to include all women with breast cancer diagnosed ≤ 65 years of age, will substantially improve the sensitivity of mutation testing, without the need for evaluation of all breast cancer patients. Table 1: Comparison of frequency of germline mutations between patients who met and did not meet NCCN guidelines for germline genetic testing#Total, Meets ASBrS guidelines N=3942Meets NCCN guidelines, N=2050Did not meet NCCN guidelines, N=1892P-value€ NCCN vs non-NCCNPercent mutation carriers missed by NCCN criteria* BRCA1/2121 (3.1%)106 (5.2%)15 (0.8%)<0.00112.4%6 High risk genes$150 (3.8%)120 (5.8%)30 (1.6%)<0.00120.0%12 Breast cancer genes:272 (6.9%)200 (9.8%)72 (3.8%)<0.00126.5%ATM45 (1.1%)32 (1.56%)13 (0.69%)28.9%BARD16 (0.2%)5 (0.24%)1 (0.05%)16.7%BRCA158 (1.5%)53 (2.59%)5 (0.26%)8.6%BRCA263 (1.6%)53 (2.59%)10 (0.53%)15.9%CDH16 (0.2%)3 (0.15%)3 (0.16%)50.0%CHEK267 (1.7%)41 (2.00%)26 (1.36%)38.8%NF10 (0.0%)0 (0.00%)0 (0.00%)0.0%PALB216 (0.4%)7 (0.34%)9 (0.48%)56.3%PTEN1 (0.0%)1 (0.05%)0 (0.00%)0.0%RAD51C6 (0.2%)6 (0.29%)0 (0.00%)0.0%RAD51D4 (0.1%)2 (0.10%)2 (0.11%)50.0%TP537 (0.2%)3 (0.15%)4 (0.21%)57.1%#: Patients who did not meet NCCN criteria excluded from analysis$: BRCA1, BRCA2, CDH1, PALB2, PTEN and TP53;€: Fisher exact test comparing frequency of germline mutations between those who met NCCN guidelines and those who did not;*: Denominators for percentages are the total mutation carriers in respective categories. Citation Format: Siddhartha Yadav, Chunling Hu, Steven N. Hart, Nicholas Boddicker, Eric C. Polley, Jie Na, Rohan Gnanaolivu, Kun Y. Lee, Janet E. Olson, Kathryn J. Ruddy, Fergus J. Couch. Comparison of recommendations for germline genetic testing in an unselected cohort of patients with breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-08-01.

Real-World Application of National Comprehensive Cancer Network (NCCN) Testing Guidelines in Diffuse Large B-Cell Lymphoma (DLBCL) Results in Underdiagnosis of Double-Hit Lymphoma

Introduction: Concurrent translocation of MYC, BCL2, and/or BCL6 (so-called double hit [DH] or triple hit [TH] disease) is associated with poor prognosis in patients with DLBCL. NCCN guidelines currently recommend immunohistochemistry (IHC) testing for MYC and BCL2 for all patients and additional testing by fluorescence in situ hybridization (FISH) or karyotype analysis in patients with both (i) IHC positive results for MYC and BCL2, and (ii) a germinal center B-cell (GCB) immunophenotype (e.g., as derived from the Hans algorithm). To investigate how well these guidelines perform in identifying DH/TH patients, we examined the prevalence of DH/TH lymphoma in a real-world population of patients with DLBCL who underwent both IHC and molecular testing. Methods: This retrospective analysis leveraged de-identified electronic health record (EHR)-derived data from the nationwide Flatiron Health database. The database included 5,747 patients who had a diagnosis of DLBCL between 1/1/2011 and 7/1/2019, as confirmed by technology-enabled chart abstraction. Additional information on cell of origin, IHC, karyotype analysis, and FISH testing was abstracted from pathology reports or clinical visit notes, where available. We then selected a cohort of patients who had a known result for each of four different tests: (1) MYC by IHC, (2) MYC by molecular testing, (3) BCL2 by IHC, and (4) either BCL2 or BCL6 by molecular testing. Where not directly stated by the physician, cell of origin was derived from abstracted IHC testing using the Hans algorithm (Hans C et al., Blood 2004; 103:275-282). Institutional Review Board approval with waiver of informed consent was obtained prior to study conduct. Results: Of 5,747 patients with DLBCL in the database, 742 were tested and had a confirmed known result for each of the qualifying tests. 417 (56%) were double expressors (DE), positive for both BCL2 and MYC by IHC, and 103 (14%) were DH/TH. Within the DH/TH sample, 64 patients (62%) were DE with a GCB-like immunophenotype, and thus would have been tested under NCCN guidelines; and 39 (38%) were not DE with a GCB-like immunophenotype, and thus would have been missed by current NCCN guidelines. Discussion: A higher-than-expected proportion of patients were DE by IHC: 56% in this series vs. up to 34% in historic series (Hu S et al., Blood 2013; 121:4021-4031). This is likely due to our cohort of patients requiring both IHC and molecular testing to have been performed, which NCCN guidelines state should only occur in DE patients with GCB-like immunophenotype. However, even in a cohort enriched with DE and GCB patients, 38% of the DH/TH patients would not have been detected with current NCCN testing guidelines, which restrict only to those who were DE with a GCB-like immunophenotype. This analysis reflects several factors encountered in real-world cohorts, such as the variability in practice patterns relative to professional guidelines, or practical challenges in the standardization of IHC testing. In order to improve the detection of DH/TH disease, guideline panels should consider expanding molecular testing to all DLBCL patients, regardless of IHC findings. Disclosures Hooley: Roche: Equity Ownership; Flatiron Health, Inc., which is an independent subsidiary of the Roche Group: Employment, Research Funding. Parrinello:Roche: Equity Ownership; Flatiron Health, Inc., which is an independent subsidiary of the Roche Group: Employment, Research Funding. Opong:Flatiron Health, Inc., which is an independent subsidiary of the Roche Group: Employment, Research Funding. Maignan:Roche: Equity Ownership; Flatiron Health Inc., which is an independent subsidiary of the Roche Group: Employment, Research Funding. Carson:Flatiron Health, Inc., which is an independent subsidiary of the Roche Group: Employment, Research Funding; Roche: Equity Ownership. Fisher:prIME: Honoraria; Barclays: Honoraria; AstraZeneca: Consultancy; Celgene: Consultancy.

Validation of a digital identification tool for individuals at risk for hereditary cancer syndromes

BackgroundThe number of individuals meeting criteria for genetic counseling and testing for hereditary cancer syndromes (HCS) is far less than the number that actually receive it. To facilitate identification of patients at risk for HCS, Counsyl developed a digital identification tool (digital ID tool) to match personal and family cancer history to National Comprehensive Cancer Network (NCCN) BRCA-related Hereditary Breast and Ovarian Cancer (HBOC), Lynch syndrome, and polyposis testing criteria in one-to-one, automated fashion. The purpose of this study was to validate the ability of the digital ID tool to accurately identify histories that do and do not meet NCCN testing criteria.MethodsThird-party recorded three-generation pedigrees were retrospectively reviewed by a certified genetic counselor (CGC) to determine if independent events included in pedigree histories met NCCN guidelines, and were then sorted into groups: high risk events (meets criteria) and low risk events (does not meet criteria). Events were entered into the digital ID tool to determine the extent of its concordance with events sorted by CGC review. Statistical tests of accuracy were calculated at a 95% confidence interval (CI).ResultsOne hundred ninety-seven pedigrees were reviewed consecutively representing 765 independent events for analysis across groups. 382/382 (100%) high risk events identified by the digital ID tool and 381/383 (99.47%) low risk events identified by the digital ID tool were concordant with CGC sorting. The digital ID tool had a sensitivity of 100% (99.04–100% CI) and specificity of 99.48% (98.13–99.94% CI). The overall accuracy of the digital ID tool was estimated to be 99.74% (99.06–99.97% CI), reflecting the rate at which the digital ID tool reached the same conclusion as that of CGC review of pedigree events for the recommendation of genetic testing for individuals at risk for HCS.ConclusionsThe digital ID tool accurately matches NCCN criteria in one-to-one fashion to identify at-risk individuals for HCS and may be useful in clinical practice, specifically for BRCA-related HBOC and Lynch Syndrome.

Abstract P3-08-04: Trends in age of breast cancer diagnosis for women with pathogenic variants in genes associated with increased breast cancer risk

Abstract Background: The National Comprehensive Cancer Network (NCCN) currently recommends consideration of genetic testing for appropriate, high risk individuals when it will impact medical management of the individual or at-risk family members. Established NCCN testing criteria are based on family history, the presence of multiple primary cancers, and age of diagnosis. For breast cancer, women diagnosed before age 50 are eligible for genetic testing with limited family history; however, these criteria were developed based on high-risk breast cancer genes, such as BRCA1 and BRCA2. The growing use of gene panels has extended testing to include genes associated with a 2- to 4-fold increased risk for breast cancer. Although NCCN guidelines now include medical management recommendations for these genes, it is unclear whether current criteria appropriately identify candidates for testing who have pathogenic variants (PVs) in genes with moderate breast cancer risk. Here, we investigated the age of breast cancer diagnosis in women carrying PVs in genes with high or moderate breast cancer risk. Methods: Clinical testing was performed for 68,239 women with a personal diagnosis of breast cancer using a 25-gene hereditary cancer panel that includes genes with a high (BRCA1, BRCA2, PTEN, TP53) or moderate (PALB2, CHEK2, ATM, STK11, CDH1, NBN, BARD1) risk of breast cancer. The majority of women tested met current NCCN criteria for testing based on their personal and/or family cancer history. The proportion of women with a PV who were diagnosed <50 and <60 years of age was evaluated. Results: Overall, 5,231 women diagnosed with breast cancer were found to carry a PV in a gene with high or moderate breast cancer risk. 70.2% of women with PVs in genes with a high breast cancer risk were diagnosed with breast cancer before age 50, compared to only 55.5% of patients with PVs in genes with moderate breast cancer risk (see Table). However, similar proportions of women with PVs in genes with a high (89.3%) and moderate (80.2%) breast cancer risk were diagnosed before age 60 (see Table). GeneDiagnosed <50Diagnosed <60Moderate Breast Cancer RiskCHEK2458 (59.3%)629 (81.5%)PALB2337 (54.7%)507 (82.3%)ATM315 (52.4%)452 (75.2%)BARD168 (51.5%)111 (84.1%)NBN56 (52.3%)86 (80.4%)CDH124 (58.5%)33 (80.5%)STK114 (66.7%)6 (100%)Total1262 (55.5%)1824 (80.2%)High Breast Cancer RiskBRCA11086 (76.4%)1314 (92.4%)BRCA2901 (63.0%)1227 (85.8%)TP5361 (83.6%)68 (93.2%)PTEN28 (90.3%)31 (100%)Total2076 (70.2%)2640 (89.3%) Conclusions: Approximately half of the women with a PV in a moderate breast cancer risk gene identified here were diagnosed before age 50. This likely overestimates the proportion of moderate-risk PV carriers with early onset breast cancers, as current testing criteria are weighted towards diagnoses at young ages. Given that there are now medical management guidelines for patients who carry PVs in most of the moderate-risk breast cancer genes, it is important to consider whether current testing criteria developed for genes with a high breast cancer risk effectively identify women with PVs in moderate-risk genes. Citation Format: Gorringe H, Rosenthal E, Kidd J, Brown K, Manley S. Trends in age of breast cancer diagnosis for women with pathogenic variants in genes associated with increased breast cancer risk [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-08-04.

Impact of Payer Constraints on Access to Genetic Testing.

With increased demand for hereditary cancer genetic testing, some large national health-care insurance payers (LNHPs) have implemented policies to minimize inappropriate testing by mandating consultation with a geneticist or genetic counselor (GC). We hypothesized such a restriction would reduce access and appropriate testing. Test cancellation rates (ie, tests ordered that did not result in a reported test result), mutation-positive rates, and turnaround times for comprehensive BRCA1/2 testing for a study LNHP that implemented a GC-mandate policy were determined over the 12 months before and after policy implementation (excluding a 4-month transition period). Cancellation rates were evaluated based on the reason for cancellation, National Comprehensive Cancer Network testing criteria, and self-identified ancestry. A control LNHP was evaluated over the same period for comparison. The study LNHP cancellation rate increased from 13.3% to 42.1% ( P < .001) after policy implementation. This increase was also observed when only individuals who met National Comprehensive Cancer Network criteria for hereditary breast and ovarian cancer testing were considered (9.5% to 37.7%; P < .001). Cancellation rates increased after policy introduction for all ancestries; however, this was more pronounced among individuals of African or Latin American ancestry, for whom cancellation rates rose to 48.9% and 49.6%, respectively, compared with 33.9% for individuals of European ancestry. Over this same time period, control LNHP cancellation rates decreased or stayed the same for all subgroups. These findings demonstrate that a GC-mandate policy implemented by a LNHP substantially decreased access to appropriate genetic testing, disproportionately impacting minority populations without any evidence that inappropriate testing was decreased.

BRCA testing within the Department of Veterans Affairs: concordance with clinical practice guidelines.

Guideline-concordant cancer care is a priority within the Department of Veterans Affairs (VA). In 2009, the VA expanded its capacity to treat breast cancer patients within VA medical centers (VAMCs). We sought to determine whether male and female Veterans diagnosed with breast cancer received BRCA testing as recommended by the National Comprehensive Cancer Network (NCCN) guidelines on Genetic/Familial High-Risk Assessment in Breast and Ovarian Cancer (v. 1.2010-1.2012). Using the 2011-2012 VA Central Cancer Registry and BRCA test orders from Myriad Genetics, we conducted a retrospective study. The outcome variable was a recommendation for genetic counseling or BRCA testing, determined by chart review. Independent variables expected to predict testing included region, site of care, and patient characteristics. We performed descriptive analysis of all patients and conducted multivariable logistic regression on patients who sought care at VAMCs that offered BRCA testing. Of the 462 Veterans who met NCCN testing criteria, 126 (27%) received guideline-concordant care, either a referral for counseling or actual testing. No BRCA testing was recommended in 49 (50%) VAMCs that provide cancer treatment. Surprisingly, patients with second primary breast cancer were less likely to be referred/tested (OR 0.39; CI 0.17, 0.89; p=0.025). For patients under age 51, a yearly increase in age decreased likelihood of referral or testing (OR 0.85; CI 0.76, 0.94; p<0.001). There were no differences in testing by race. In conclusion, there was significant underutilization and lack of access to BRCA testing for Veterans diagnosed with breast cancer. Our research suggests the need for clinical decision support tools to facilitate delivery of guideline-concordant cancer care and improve Veteran access to BRCA testing.

Abstract P2-09-21: HBOC genetic counseling: A genetic counselor-physician partnership model

Abstract Background: In 2003, the American Society of Clinical Oncology (ASCO) issued a policy statement that addressed the oncologist's role in integrating cancer genetic risk assessment and management into clinical practice. ASCO supports access to genetic counseling for patients offered genetic testing and after results disclosure. In 2014, Integrated Genetics (IG) began offering genetic counseling in partnership with OBGYNs and oncologists whose patients have a personal or family history of breast or ovarian cancer. The goal of the program was to provide an easily accessible and comprehensive genetic counseling service for Hereditary Breast and Ovarian Cancer (HBOC) to meet the needs of patients and to support clinicians who currently provide pre- and post-test counseling. Methods: In this study we describe IG's HBOC genetic counseling service and in a retrospective analysis, describe the characteristics of patients referred to the program in 2014. Clinicians were provided a toll free number for patients to call to schedule a genetic counseling session. The scheduling staff facilitated medical record requests and emailed a family history questionnaire. In person or telegenetic counseling (via WebEx) was offered. Telegenetic counseling allowed the patient and genetic counselor to see one another via webcam and view counseling visual aids and relevant medical records. Pedigree analysis and cancer genetic risk assessment were performed and genetic testing options discussed based on National Comprehensive Cancer Network (NCCN) testing criteria. Information discussed at the session, including patient decisions about testing, was documented for the referring physician and patient in the Genetic Counseling Consultation Report. The physician ordered testing and managed patient screening and surveillance. Results: During 2014, 247 counseling sessions were provided to patients from 23 states. All patients had a personal or family history of breast or ovarian cancer and the average age of patients was 44 years (range: 16-85). Sixty four percent (64%) of sessions were done via WebEx and 36% in person. Of the 247 sessions, 198 (80.2%) were for pre-test genetic counseling; of those, 173 (87.4%) met NCCN HBOC genetic testing criteria and genetic testing for BRCA1/2 was offered. Of this group, 70.52% desired testing, 27.75% declined and 1.73% were undecided. The remaining sessions (n=49) included post-test counseling for pathogenic mutations or variants of unknown significance (n=39), and patients who had accepted testing but whose results were pending (n=10). Conclusions: The IG HBOC genetic counseling program extended comprehensive genetic counseling to patients at increased risk for BRCA1/2 mutations who might not otherwise have access to this service. Physicians appropriately selected patients for referral (87% met NCCN testing criteria). The genetic counselors provided cancer genetic risk assessment, time-intensive patient education to facilitate informed decision making, and counseling about the implications of results, including the complexities of variants of unknown significance. This partnership model allowed physicians to retain patient care oversight, including management of screening and surveillance, while leveraging genetic counselor expertise. Citation Format: Oliver JB, Cronister A. HBOC genetic counseling: A genetic counselor-physician partnership model. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-09-21.

Molecular Testing in Anatomic Pathology and Adherence to Guidelines: A College of American Pathologists Q-Probes Study of 2230 Testing Events Reported by 26 Institutions.

The appropriate and timely performance of molecular testing in anatomic pathology is an indicator of quality. The National Comprehensive Cancer Network (NCCN) publishes a comprehensive treatment guideline that includes recommendations for ancillary testing. To establish benchmarks for rates of adherence to NCCN testing recommendations through a multi-institutional study. Participants in a 2013 Q-Probes study of the College of American Pathologists reported data from molecular testing on anatomic pathology cases, excluding hematolymphoid neoplasms, breast primary carcinomas, and gynecologic cytology. Twenty-six institutions reported data from 2230 molecular testing events. In a retrospective study limited to colon, lung, and melanoma, there was strict adherence to guidelines in a median 71% (10th to 90th percentile range, 33%-90%) and there was at least loose adherence in a median 95% (10th to 90th percentile range, 57%-100%). There was adequate tissue to complete testing in a median 98% (10th to 90th percentile range, 86%-100%); in aggregate the adequacy rate for cell blocks was lower (84%, P < .001). Median test turnaround time was 8 days (10th to 90th percentile range, 4-13 days). In a prospective collection of all organ sites, there was strict adherence to guidelines in a median 53% (10th to 90th percentile range, 20%-71%), and there was at least loose adherence in a median 94% (10th to 90th percentile range, 75%-100%). Adherence to guidelines was higher for lung specimens and in institutions with more multidisciplinary conferences. This multi-institutional study provides benchmarking data on appropriateness and timeliness of molecular testing in anatomic pathology.

Prevalence of BRCA mutations in an unselected population of triple‐negative breast cancer

This study assessed BRCA1 and BRCA2 mutation prevalence in an unselected cohort of patients with triple-negative breast cancer (BC). One hundred ninety-nine patients were enrolled. Triple negativity was defined as <1% estrogen and progesterone staining by immunohistochemistry and HER-2/neu not overexpressed by fluorescence in situ hybridization. Having given consent, patients had BRCA1 and BRCA2 full sequencing and large rearrangement analysis. Mutation prevalence was assessed among the triple-negative BC patients and the subset of patients without a family history of breast/ovarian cancer. Independent pathological review was completed on 50 patients. Twenty-one deleterious BRCA mutations were identified--13 in BRCA1 and 8 in BRCA2 (prevalence, 10.6%). In 153 patients (76.9%) without significant family history (first-degree or second-degree relatives with BC aged <50 years or ovarian cancer at any age), 8 (5.2%) mutations were found. By using prior National Comprehensive Cancer Network (NCCN) guidelines recommending testing for triple-negative BC patients aged <45 years, 4 of 21 mutations (19%) would have been missed. Two of 21 mutations (10%) would have been missed using updated NCCN guidelines recommending testing for triple-negative BC patients aged <60 years. The observed mutation rate was significantly higher (P = .0005) than expected based on previously established prevalence tables among patients unselected for pathology. BRCA1 mutation prevalence was lower, and BRCA2 mutation prevalence was higher, than previously described. Additional mutation carriers would have met new NCCN testing guidelines, underscoring the value of the updated criteria. Study data suggest that by increasing the age limit to 65 years, all carriers would have been identified.