Jennifer Saam

A study of over 35,000 women with breast cancer tested with a 25-gene panel of hereditary cancer genes

As panel testing becomes more common in clinical practice, it is important to understand the prevalence and trends associated with the pathogenic variants (PVs) identified. This is especially true for genetically heterogeneous cancers, such as breast cancer (BC), in which PVs in different genes may be associated with various risks and cancer subtypes. The authors evaluated the outcomes of genetic testing among women who had a personal history of BC.

Validation of a Molecular and Pathological Model for Five-Year Mortality Risk in Patients with Early Stage Lung Adenocarcinoma

Introduction: The aim of this study was to validate a molecular expression signature [cell cycle progression (CCP) score] that identifies patients with a higher risk of cancer-related death after surgical resection of early stage (I-II) lung adenocarcinoma in a large patient cohort and evaluate the effectiveness of combining CCP score and pathological stage for predicting lung cancer mortality. Methods: Formalin-fixed paraffin-embedded surgical tumor samples from 650 patients diagnosed with stage I and II adenocarcinoma who underwent definitive surgical treatment without adjuvant chemotherapy were analyzed for 31 proliferation genes by quantitative real-time polymerase chain reaction. The prognostic discrimination of the expression score was assessed by Cox proportional hazards analysis using 5-year lung cancer-specific death as primary outcome. Results: The CCP score was a significant predictor of lung cancer-specific mortality above clinical covariates [hazard ratio (HR) = 1.46 per interquartile range (95% confidence interval = 1.12–1.90; p = 0.0050)]. The prognostic score, a combination of CCP score and pathological stage, was a more significant indicator of lung cancer mortality risk than pathological stage in the full cohort (HR = 2.01; p = 2.8 × 10−11) and in stage I patients (HR = 1.67; p = 0.00027). Using the 85th percentile of the prognostic score as a threshold, there was a significant difference in lung cancer survival between low-risk and high-risk patient groups (p = 3.8 × 10−7). Conclusions: This study validates the CCP score and the prognostic score as independent predictors of lung cancer death in patients with early stage lung adenocarcinoma treated with surgery alone. Patients with resected stage I lung adenocarcinoma and a high prognostic score may be candidates for adjuvant therapy to reduce cancer-related mortality.

Comprehensive sequencing of PALB2 in patients with breast cancer suggests PALB2 mutations explain a subset of hereditary breast cancer

This study sought to determine the prevalence of PALB2 mutations in a cohort referred for diagnostic testing for hereditary breast cancer.

Hereditary Cancer-Associated Mutations in Women Diagnosed with Two Primary Cancers: An Opportunity to Identify Hereditary Cancer Syndromes after the First Cancer Diagnosis

Objectives: Patients with hereditary cancer syndromes are at high risk for a second primary cancer. Early identification of these patients after an initial cancer diagnosis is the key to implementing cancer risk-reducing strategies. Methods: A commercial laboratory database was searched for women with a history of both breast and ovarian or colorectal and endometrial cancer who underwent genetic testing for hereditary breast and ovarian cancer (HBOC) or Lynch syndrome (LS). Results: Among women with both breast and ovarian cancer, 22.4% (2,237/9,982) had a BRCA1 or BRCA2 mutation. Among women with both colorectal and ovarian cancer, 28.1% (264/941) had a mutation associated with LS. In 66.6% of BRCA1 or BRCA2 mutation carriers and in 58.3% of LS mutation carriers, >5 years passed between the cancer diagnoses. Of patients with HBOC and LS, 56 and 65.2%, respectively, met the National Comprehensive Cancer Network guidelines for hereditary cancer testing after their initial diagnosis based on their personal cancer history alone. Conclusions: A substantial number of women tested for LS or HBOC after being diagnosed with two successive primary cancers were diagnosed with a hereditary cancer syndrome. In many cases, the time interval between the diagnoses was long enough to allow for the implementation of surveillance and/or prophylactic measures.

Patients Tested at a Laboratory for Hereditary Cancer Syndromes Show an Overlap for Multiple Syndromes in Their Personal and Familial Cancer Histories.

Objective: Hereditary cancer testing guidelines are based on the premise that the common hereditary cancer syndromes have distinct, recognizable phenotypes. However, many syndromes present with overlapping cancers. The aim of this analysis was to identify the proportion of patients tested for Lynch syndrome (LS) or hereditary breast and ovarian cancer (HBOC) who met testing criteria for the other syndrome. Method: We analyzed a commercial laboratory database of patients tested for LS and HBOC in a clinical setting from 2006 to 2013. Patient cancer histories were analyzed using the 2012 NCCN criteria for LS and the 2013 NCCN criteria for HBOC. Results: In all, 7% of the patients tested for HBOC met criteria for LS testing. The majority of these patients had a family history of colorectal (30.9%) and/or endometrial cancer (22.7%). Conversely, 29.5% of the patients tested for LS met criteria for HBOC testing. In this group, 30.5% of the patients had a personal history of breast cancer, and 12.6% had a personal history of ovarian cancer. Conclusions: Our data demonstrate a substantial phenotypic overlap among patients for multiple common inherited cancer syndromes, which likely complicates diagnosis and test selection. This supports the value of multigene panels to identify pathogenic mutations in the absence of a clinically specific phenotype.

Mutation analysis of PALB2 in high-risk and lower-risk patients negative for BRCA1 and BRCA2 mutations.

30 Background: PALB2 has been identified as a breast cancer susceptibility gene conferring ~ 2-4 fold increased risk of breast cancer. A number of studies have estimated the PALB2 mutation prevalence to range from 0.5% - 2.9% in populations of breast cancer patients. We performed an analysis to determine the PALB2 mutation prevalence in a large U.S. referral testing population. METHODS DNA samples were anonymized from two subsets of patients: 955 early onset breast cancer patients with severe family history, and 524 patients with later onset of breast cancer and/or less severe family history. All patients were negative for deleterious sequence mutations or large rearrangements in BRCA1 and BRCA2. RESULTS We identified 10 disease associated PALB2 mutations in the high risk group of 955 patients and 2 deleterious PALB2 mutations in the lower risk group of 524 patients. Identified PALB2 mutations included 8 nonsense, 3 frameshift mutations and a splice site mutation. The mutation prevalence for the high risk population was 1.05% (95% C.I., 0.5 -1.92) whereas that for the lower risk population was 0.38% (95% C.I., 0.05-1.37). The observed rate of PALB2 variants of unknown significance (VUS) identified in this study was ~5% (78 VUS were in 75 of the 1479 patients that were tested). Our variant classification program which successfully decreased the VUS rate in BRCA1 and BRCA2 is similarly expected to enhance mutation classification on an on-going basis for PALB2 genetic testing. CONCLUSIONS Genetic testing for PALB2 may be indicated as a reflex test for breast cancer patients who test negative for BRCA1 and BRCA2.

Stratification of risk for patients with prostate cancer at biopsy using CCP score.

127 Background: In the US, most prostate cancers are treated with surgery or radiation, despite many having low malignant potential. If low cancer progression risk can be established, some men can be spared treatment. PSA, Gleason score and clinical stage work well for population risk assessment but lack precision for individuals. Molecular analysis can refine risk assessment as demonstrated by a cell cycle progression score (CCP) predictive of prostate cancer aggressiveness in 4 separate cohorts. In these studies, CCP typically ranged from -2 to +3 with each 1-unit increase corresponding to approximately a doubling of risk. We characterized the CCP distribution using recent samples from a typical US urology multi-centered clinical setting and determined the analytic success rate of the assay. METHODS Formalin fixed, prostate biopsy tissue from 300 patients diagnosed with adenocarcinoma within the last 12 months was analyzed. CCP is calculated by measuring the relative RNA expression of 31 cell cycle progression genes. Patients were recruited from 15 geographically diverse community urology practices. RESULTS CCP could be measured for 98% of samples (294/300). This study showed a normal distribution for the CCP ranging from -2 to 3.2 (median = -0.3, SD=0.92). There was little correlation of CCP with PSA, age, or body mass index. Correlation with Gleason score was similar to those in prior studies (r=0.494). A relative classification of cancer aggressiveness based on CCP of ~ 1200 patients from multiple cohorts has been developed. The 294 evaluable patients were cross-classified by AUA risk and cancer aggressiveness (see table). CCP further stratified patients within each AUA risk classification. CONCLUSIONS CCP is a novel assay that can facilitate risk stratification for men with prostate adenocarcinoma. [Table: see text].

Abstract PD7-03: Characterization of Li-Fraumeni syndrome diagnosed using a 25-gene hereditary cancer panel

Background: Clinical diagnostic criteria for Li-Fraumeni syndrome (LFS) have evolved with increased utilization of TP53 germline testing and subsequent improved understanding of the diversity of the associated cancer phenotypes. However, data on LFS still suffer from ascertainment bias as patients are typically selected to undergo TP53 testing based on the presence of hallmark features of LFS. Analyzing TP53 mutation carriers identified from multi-gene panel testing, for which the diagnosis of LFS may not have been suspected or was included in a longer differential diagnosis, affords an opportunity to characterize additional TP53 carriers who might not otherwise have been ascertained. Methods: Patients with a deleterious or suspected deleterious germline TP53 mutation were identified from 80,748 consecutive cases that underwent a 25-gene hereditary cancer panel test between September 2013 and March 2015 at a commercial diagnostic laboratory. Patient clinical data were obtained by healthcare provider report on test requisition forms. Each TP53 mutation carrier was evaluated to determine whether the National Comprehensive Cancer Network9s (NCCN) guidelines were met for TP53 testing. Results: Eighty-one TP53 mutation carriers were identified and had a total of 115 cancers (0.1% overall prevalence). Among the 76 carriers with at least one cancer, the average age at first diagnosis was 42 years (range 11-76 years) and 24% were first diagnosed older than age 50 years. The most common first cancers were of the breast (n=45), ovary (n=9), and gastrointestinal tract (n=8). Fifty-two of the 75 (69%) women had breast cancer, 44% of which were first diagnosed at 35 years or younger, and 21% were first diagnosed at 50 years or older. Only 27 TP53 carriers met NCCN criteria for TP53 testing, 14 of whom only met based on having early-onset breast cancer. An additional 8 did not meet criteria themselves but had a first- or second-degree relative who did. Among the 28 individuals with more than one primary cancer, 21 (75%) developed their second primary at a site for which increased surveillance is recommended in LFS, but only 4 would have met NCCN criteria for TP53 testing at their first cancer diagnosis. The most common second cancers were of the breast (n=16), gastrointestinal tract (n=4), or kidney (n=2) and occurred an average of 11 years after the first cancer (range 0-36 years). Conclusion: In this analysis, a large proportion of carriers would not have been identified as TP53 testing candidates based on NCCN guidelines. Our data are consistent with other studies demonstrating high second primary cancer risks in LFS, and highlight the value of multigene panel testing in identifying individuals who may be candidates for increased surveillance and/or cancer risk-reducing management options. Citation Format: Rich T, Lotito M, Kidd J, Saam J, Lancaster J. Characterization of Li-Fraumeni syndrome diagnosed using a 25-gene hereditary cancer panel. [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 PD7-03.

Abstract P3-10-06: Genetic testing for HBOC among women with a personal diagnosis of breast cancer in patients with Medicaid as compared to patients with private insurance

Introduction: National guidelines recommend that women diagnosed with early-onset breast cancer and/or a strong family history receive BRCA1/2 testing to guide treatment decisions. Among newly diagnosed patients, a positive test result will often prompt more aggressive surgical treatment to minimize the risk of second primary cancers. Currently, coverage for genetic counseling and testing for Hereditary Breast and Ovarian Cancer (HBOC) under the Medicaid expansion program of the Affordable Care Act has varied by state, where some states require a copayment for this service. Similarly, there is no mandate to cover risk-reducing surgery for patients found to carry a genetic mutation despite research showing cost-effectiveness. This analysis sought to determine whether genetic testing for HBOC among patients with breast cancer is different for those with Medicaid compared to those with private insurance. Methods: A commercial laboratory database was analyzed for patients with a personal history of breast cancer who underwent testing with a 25-gene hereditary cancer panel from September 2013-February 2016. Patients were eligible for inclusion if they were between ages 18 and 64 at the time of testing and had not undergone previous genetic testing. A total of 17,020 patients with either Medicaid (N=4,313) or one of 5 private payers (N=12,707) were tested during this period. Descriptive statistics, including means for continuous variables and proportions for categorical variables, were calculated. Chi-square tests were used to test associations and differences of positive rates between insurance provider category. Two-tailed p-values are reported, and any p-value less than 0.05 is considered statistically significant. Results: Medicaid patients had a median age of breast cancer diagnosis of 45 compared to 47 for patient with private insurance. Among women with Medicaid insurance, a higher proportion were of African (13.3% vs 6.4%) and Latin American ancestry (16.4% vs 5.3%). The mutation positive rate among patients with Medicaid was 13.0%, which was statistically higher than patients with private insurance (9.5%) (p Conclusions: Overall, the positive mutation rate among individuals with Medicaid insurance was higher than those with private insurance, suggesting the testing requirements applied to this population may be more stringent than those applied to the private insurance population. Consistent genetic testing insurance criteria are necessary for all patients to receive care in line with guidelines following a breast cancer diagnosis. Citation Format: Baron P, Johnson-Isidore K, Miller L, Brown K, Kidd J, Saam J, Lancaster J. Genetic testing for HBOC among women with a personal diagnosis of breast cancer in patients with Medicaid as compared to patients with private insurance [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 P3-10-06.

Lynch Syndrome Patients with Limited Family History Identified in a Laboratory Setting: A Descriptive Study

Objective: Patients diagnosed with colorectal cancer before the age of 50 years are recommended for Lynch syndrome (LS) testing according to current clinical guidelines. However, many patients are not identified because of the stringent guidelines on existing diagnostic criteria. The aim of this analysis was to evaluate the ability of existing criteria to adequately ascertain patients appropriate for LS genetic testing. Method: To determine whether existing clinical diagnostic criteria underascertain individuals who would be appropriate candidates for hereditary cancer risk assessment, we stratified the detection rate of deleterious mismatch repair (MMR) mutations in 9,109 patients with a personal history of colorectal cancer who were diagnosed between the ages of 30 and 74 years with little or no family history suggestive of LS by 5-year age-at-detection intervals. Results: There was little difference in the aggregate positive mutation rate in individuals diagnosed between the ages of 50 and 59 years compared to the positive mutation rate in patients diagnosed before the age of 50 years. Conclusion: These results suggest that cancer diagnosis under the age of 50 years is an insufficiently sensitive predictor of hereditary cancer susceptibility.