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Background: With the rise of genomic testing, more clinicians are using panels to understand the genetic profile of breast cancer to help aid in clinical management. However, little is known about the relationship between the results of genomic tests and the likelihood of identifying an underlying germline variant, and how this should integrate into clinical decision making. Methods: Data was obtained from the Informed Genetics Annotated Patient Registry (iGAP), an IRB-approved, multi-centered longitudinal registry designed to capture biomarker test results and their impact on treatment practices and outcomes. Two genomic tumor profiling tests were studied - MammaPrint recurrence risk and Blueprint molecular subtypes, including Luminal type A, Luminal type B, Basal, and HER 2 type. Of the 3400 patients currently enrolled in the registry, 528 have been diagnosed with breast cancer and underwent tumor profiling by both MammaPrint and BluePrint as well as germline genetic testing, including analyses of 24 cancer susceptibility genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, NBN, PALB2, PTEN, STK11, TP53, APC, BMPR1A, CDK4, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, RAD51C, RAD51D, SMAD4). Differences in positive germline variant rates were tested for with two-sided, Chi-Square tests using the prop.test function in R. Results: 231 (44.17%) were classified as High-Risk for recurrence on MammaPrint, with a 0.13 PVs detected per patient tested (positive germline variant (PV) Rate), 269 (51.34%) were identified as having a Low-Risk, with a 0.0849 PV rate, and 23 (4.4%) Ultra-Low-Risk, with a 0.0455 PV rate. There is not a significant difference between the High-Risk and Low-Risk for recurrence (p=0.09). 45 (8.54%) Basal molecular subtype identified by BluePrint panel, with a 0.1778 PV rate, 292 (55.41%) classified as Luminal A type, with a 0.0819 PV rate, 171 (32.45%) Luminal B with 0.1078 PV rate, and 13 (2.47%) HER2 Type with 0.07 PV rate. There was a significant difference between Basal and Luminal A PV rates (p=0.042), but no other statistically significant differences were found. Conclusions: Patients with a Basal molecular subtype have a significantly higher likelihood of having a germline pathogenic variant compared to Luminal A subtype. There was a trend that did not reach statistical significance for MammaPrint High Risk to have a higher likelihood of germline pathogenic result compared to MammaPrint Low Risk. This data adds another parameter for germline testing in those breast cancer patients who fall outside of current NCCN testing criteria. Citation Format: Peter Beitsch, Chloe Wernecke, Rakesh Patel, Barry Rosen, Eric Brown, Gia Compagnoni, Ian Grady, Lindsay Gold, Pat Whitworth, Linda Ann Smith, Mariusz Wirga, Richard Reitherman, Steven Cai, Toan Nguyen, Valerie Traina, Dennis Holmes, Paul Baron, Brittany Krautheim, Anne Peled, Walt Taylor, Kelly Bontempo, Brenna Bentley, Krista Ortega, Pouyan Ahmadi. Germline Testing Results in Patients with Genomic Tumor Profiling [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-43.

Background: Genetic resources are underutilized when it comes to being incorporated into a breast cancer patient’s treatment, but that isn’t the only piece being overlooked. The Ki-67 proliferation index expressed (Ki-67%) is an established marker of tumor proliferation and aggressive behavior. We hypothesized that Ki-67% could have increased clinical utility when correlated with genomic testing results. Methods: Data was obtained from the Informed Genetics Annotated Patient Registry (iGAP), an IRB-approved, multi-center longitudinal registry designed to capture biomarker test results and their impact on treatment practices and outcomes. Tumor grades and Ki-67% were taken from patient pathology reports. The average Ki-67% was then calculated and compared for each tumor grade, MammaPrint genomic recurrence risk category (ultra low risk, low risk, and high risk), and Blueprint molecular subtype (Luminal type A, Luminal type B, Basal, and HER 2 type). ANOVA statistical analysis was performed for significance values. Results: Of 3102 patients enrolled in the iGAP Registry, 733 were diagnosed with breast cancer and had available tumor grade and Ki-67% data. Among these patients, 357 had genomic recurrence risk (MammaPrint) and 220 genomic molecular subtyping (BluePrint) reports. As expected, tumor grades were significantly positively correlated with Ki-67% (p< 0.0001 between all 3 tumor grade groups). Average Ki-67% in each genomic recurrence risk revealed a significant difference between Low Risk (14%, range 1-70%) and High Risk (36%, range 1-95%, p< 0.0001). Among the genomic molecular subtypes, there were significant differences in Ki-67% between Basal (avg 69%, 17-95%) and Luminal type A (avg 13%, 1-70%, p< 0.0001)) and all other subtypes, while Luminal type B (avg 24%, 1-80%) and HER 2 (avg 38%, 29-45%) were not significantly different from each other (p=0.2817), but still significantly different to all other subtypes. Conclusion: From these results, we can deduce that molecular subtype correlates with, but is clinically distinct from, Ki-67 proliferation index. These results also indicate that molecular subtype correlates with higher tumor grades, possibly due to increased cell proliferation. Achieving truly personalized clinical decision making requires utilizing multiple modalities and biomarkers, integrating the results into management. Citation Format: Chloe Wernecke, Krista Ortega, Kelly Bontempo, Brenna Bentley, Christina Hoyer-Kimura, Peter Beitsch, Rakesh Patel, Barry Rosen, Gia Compagnoni, Ian Grady, Eric Brown, Lindsay Gold, Pat Whitworth, Linda Ann Smith, Richard Reitherman, Mariusz Wirga, Steven Cai, Toan Nguyen, Valerie Traina, Dennis Holmes, Paul Baron, Brittany Krautheim, Anne Peled, Walt Taylor. Genomic testing and Ki-67 Percentage: Two puzzle pieces being undervalued in breast cancer treatment [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-44.

Background: Racial/ethnic disparities in minority access to genetic testing have perpetuated a higher likelihood of identifying an uncertain result in minority populations. Methods :Patient data was obtained from the Informed Genetics Annotated Patient Registry (iGAP), an IRB-approved multi-center longitudinal, observational study designed to capture genetic and genomic test results and their utilization and impact on treatment practices and outcomes. Patients self-declare race/ethnicity. Genetic panels contained between 1 and 148 genes and variant classification was determined by the performing genetic testing companies and reported as negative, variant of uncertain significance (VUS),likely-pathogenic, or pathogenic. Descriptive statistics were used to assess and compare data of these populations and germline genetic testing results indicating variant of uncertain significance. Results: The three racial/ethnic groups have similar percentages of BRCA1 and BRCA2pathogenic variants. However, Caucasians have considerably more pathogenic variants in lesser penetrant genes [see Table 1]. Conclusions: Racial/ethnic groups vary by volume of lesser penetrant genes with Caucasians having the highest numbers. Correlation by SNP heritage assignment may lead to a better understanding of these differences. Gene NameAshkenazi PV% Askenazi PVs% of PV subjects AshkenaziAshkenazi VUS%VUS Ashkenazi VUS% of subjects VUS AshkenaziAsian% Asian PVs% of PV subjects AsianAsian VUS%VUS Asian mutations% of subjects VUS AsianBlack/African% Black/African PVs% of PV subjectsBlack/AfricanBlack/African VUS%VUS Black/Africanmutations% of subjects VUSBlack/AfricanCaucasian% Caucasian PVs% of PV subjects CaucasianCaucasian VUS% Caucasian Mutations% of subjects VUS CaucasianHispanic% Hispanic PVs% of PV subjects HispanicHispanic VUS% Hispanic Mutations% of subjects VUS HispanicOther% Other PVs% of PV subjects OtherOther RE VUS% Other RE Mutations% of subjects VUS Other#PV Total% Total PV#VUS TotalBRCA20.00%0.00%0.00%0.00%125.00%25.00%24.17%4.26%531.25%31.25%34.62%4.76%3414.47%16.50%122.42%2.44%815.69%18.18%45.26%5.48%211.11%12.50%36.67%6.82%5014.97%24BRCA1327.27%30.00%0.00%0.00%0.00%0.00%36.25%6.38%318.75%18.75%23.08%3.17%177.23%8.25%91.81%1.83%1631.37%36.36%11.32%1.37%211.11%12.50%24.44%4.55%4112.28%17CHEK20.00%0.00%112.50%12.50%0.00%0.00%12.08%2.13%0.00%0.00%0.00%0.00%2711.49%13.11%51.01%1.02%11.96%2.27%0.00%0.00%15.56%6.25%12.22%2.27%298.68%8ATM19.09%10.00%0.00%0.00%0.00%0.00%510.42%10.64%0.00%0.00%812.31%12.70%218.94%10.19%346.85%6.92%35.88%6.82%911.84%12.33%0.00%0.00%36.67%6.82%257.49%59CHEK2/1100delC19.09%10.00%0.00%0.00%0.00%0.00%12.08%2.13%0.00%0.00%0.00%0.00%104.26%4.85%30.60%0.61%23.92%4.55%22.63%2.74%0.00%0.00%0.00%0.00%133.89%6MUTYH0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%114.68%5.34%51.01%1.02%11.96%2.27%22.63%2.74%15.56%6.25%12.22%2.27%133.89%8PALB20.00%0.00%0.00%0.00%0.00%0.00%12.08%2.13%0.00%0.00%0.00%0.00%72.98%3.40%71.41%1.43%35.88%6.82%11.32%1.37%15.56%6.25%12.22%2.27%113.29%10BLM19.09%10.00%0.00%0.00%0.00%0.00%48.33%8.51%0.00%0.00%34.62%4.76%93.83%4.37%112.22%2.24%0.00%0.00%22.63%2.74%0.00%0.00%0.00%0.00%102.99%20MITF0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%83.40%3.88%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%82.40%0NBN0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%11.54%1.59%83.40%3.88%40.81%0.81%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%82.40%5FH327.27%30.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%41.70%1.94%40.81%0.81%0.00%0.00%11.32%1.37%0.00%0.00%0.00%0.00%72.10%5MSH619.09%10.00%112.50%12.50%0.00%0.00%0.00%0.00%0.00%0.00%4.62%4.76%31.28%1.46%132.62%2.65%23.92%4.55%22.63%2.74%15.56%6.25%0.00%0.00%72.10%19MUTYH-Biallelic/Compound Heterozygous0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%52.13%2.43%10.20%0.20%11.96%2.27%0.00%0.00%15.56%6.25%0.00%0.00%72.10%1MUTYH-Monoallelic0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%16.25%6.25%0.00%0.00%52.13%2.43%0.00%0.00%11.96%2.27%0.00%0.00%0.00%0.00%0.00%0.00%72.10%0PMS219.09%10.00%112.50%12.50%0.00%0.00%0.00%0.00%16.25%6.25%11.54%1.59%52.13%2.43%51.01%1.02%0.00%0.00%33.95%4.11%0.00%0.00%0.00%0.00%72.10%10Other00.00%0.00%562.50%62.50%375.00%75.00%3164.58%65.96%531.25%31.25%4467.69%69.84%6125.96%29.61%38377.22%78.00%1325.49%29.55%4964.47%67.12%950.00%56.25%3475.56%77.27%9127.25%546Grand Total11PV Ash108VUS Ash84PV Asi448Asi VUS4716PV Bla1665VUS Bla63235PV Cau206496VUS Cau49151PV His4476VUS His7318PV Oth1645VUS Oth44334334 PV Mutations Found738 Citation Format: Peter Beitsch, Chloe Wernecke, Kelly Bontempo, Brenna Bentley, Maureen Graham, Pat Whitworth, Rakesh Patel. Racial and ethnic groups have different clustering of common cancer genes [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-14-19.

Background:Racial/ethnic disparities in minority access to genetic testing have perpetuated a higher likelihood of identifying an uncertain result in minority populations. Methods:Patient data was obtained from the Informed Genetics Annotated Patient Registry (iGAP), an IRB-approved multi-center longitudinal, observational study designed to capture genetic and genomic test results and their utilization and impact on treatment practices and outcomes. Patients self-declare race/ethnicity. Genetic panels contained between 1 and 148 genes and variant classification was determined by the performing genetic testing companies and reported as negative, variant of uncertain significance (VUS), likely-pathogenic, or pathogenic. Descriptive statistics were used to assess and compare data of these populations and germline genetic testing results indicating variant of uncertain significance. Results:Hispanic and African American patients had approximately twice as many uncertain results (VUS) compared to Caucasian patients for all cancer genes examined. Conclusions:Variant adjudication has disproportionately sorted out more uncertain results in Caucasians than Hispanics and African Americans. This leads to greater uncertainty in post-test counseling for these groups and should be a focus for lab testing companies going forward. Citation Format: Peter Beitsch, Chloe Wernecke, Kelly Bontempo, Brenna Bentley, Maureen Graham, Pat Whitworth, Rakesh Patel. Racial and ethnic groups have different clustering of variants of uncertain significance [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-14-20.

Background:Uncovering germline genetic variants responsible for cancer predisposition allows providers to implement personalized medical care for patients. Guidelines were designed to help identify individuals who qualify for genetic testing, yet multiple studies have shown that approximately half of patients with P/LP variants are missed using these guidelines. While guidelines have continued to evolve as more robust data have become available, patients who do not meet these guidelines may not be identified as having a cancer predisposition syndrome. In studies focusing on patients with multiple cancer subtypes, comparisons of universal genetic testing versus guideline-directed for patients revealed a 12.5% likelihood of a pathogenic germline variant. This has also been studied specifically in patients with colorectal cancer, revealing that 15.5% of affected individuals have an identifiable pathogenic variant. As research continues to evaluate universal testing in oncology, it is increasingly evident that we are approaching pathogenic variant carrier frequencies that argue for a more aggressive expansion of guidelines. This has been the catalyst for recommending germline genetic testing for all patients with breast cancer. However, as insurance companies and national guidelines do not yet support this recommendation, here we set out to examine the mutation rate in all patients with breast cancer versus patients with breast cancer diagnosed at or before age 65 years. Methods:Patient data was obtained from the Informed Genetics Annotated Patient Registry (iGAP), an IRB-approved multi-center longitudinal, observational study designed to capture genetic and genomic test results and their utilization and impact on treatment practices and outcomes. Descriptive statistics were used to assess and compare data of these populations and germline genetic testing results. Results:Of the 1,302 subjects currently enrolled in the registry, 1,132 have been diagnosed with any cancer type (86.89%), of which 868 have specifically been diagnosed with breast cancer (76.657%). Results indicate that 19.04% of individuals (1 in 4.56) with any cancer type have a germline pathogenic or likely-pathogenic variant associated with cancer predisposition and/or implications for reproduction. Specific to breast cancer, results indicate that 17.74% of individuals (1 in 5.6) harbor a germline pathogenic or likely-pathogenic variant with these same implications. Of the patients with breast cancer, 71.54% were diagnosed prior to age 65 years, while 28.45% were diagnosed at or above age 65 years. 108 patients diagnosed before age 65 years had a P/LP (70.12%) while 46 diagnosed at or above age 65 years had a P/LP variant (29.87%). Conclusion:The iGAP real-world evidence database reveals 17.74% (1 in 5.6) of individuals with breast cancer harbor a pathogenic or likely-pathogenic variant in the germline with implications for medical management and/or reproduction. Given the implications these results can have on patients’ and family members’ health, testing guidelines for breast cancer should be expanded so those with hereditary predispositions can be identified and make informed decisions about preventative measures to reduce risks for a second cancer and overall mortality. Identifying those pathogenic/likely-pathogenic variants also allows for cascade testing of at-risk, likely unaffected relatives, helping reduce overall cancer incidence in the general population. Additionally, since cancer predisposition genes can also confer reproductive implications related to autosomal recessive disorders, expanding testing guidelines can arm patients with additional information that can aid in reproductive decision making. Citation Format: Kelly Bontempo, Chloe Wernecke, Caitlin Mauer, Brenna Bentley, Maureen Graham, Pat Whitworth, Rakesh Patel, Peter Beitsch. Real-world evidence database reveals 17.74% of individuals with breast cancer harbor a germline pathogenic or likely-pathogenic variant with implications for medical management and/or reproduction [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-07-03.

Background: Each year there are approximately 281,550 new cases of breast cancer.1 With the rise of somatic testing, more physicians are using panels to understand the genetic profile of breast cancer to help aid in clinical management. Agenida, a molecular diagnostics company focused on breast cancer, has developed two tests to support clinical decisions. MammaPrint analyzes 70 genes associated with breast cancer recurrence and reports whether an individual has a low (1.3%) or high (11.7%) risk for recurrence. BluePrint analyzes 80 genes to identify the breast cancer’s molecular subtype: Luminal A (low-risk), Luminal B (high-risk), HER2 (respond well to HER2-targeted therapies), and Basal-Type (aggressive subtype). However, little is known about the relationship between the results of Agendia’s tests and the likelihood of identifying an underlying germline variant. We hypothesize that individuals in the High-Risk category on MammaPrint, and individuals with Basal subtype are more likely to have positive germline genetic results indicating the presence of a pathogenic or likely pathogenic variant. Methods: Patient data was obtained from the Informed Genetics Annotated Patient Registry (iGAP), an IRB-approved multi-centered longitudinal, observational study designed to capture genetic and genomic test results and their utilization and impact on treatment practices and outcomes to help determine the most effective use of testing in real-world patient populations and to support access to advances in precision medicine. Of the 1,302 subjects currently enrolled in the registry, 868 have been diagnosed with breast cancer (66.67%). 170 individuals underwent tumor profiling through Agendia’s MammaPrint and BluePrint tests as well as germline genetic testing. Descriptive statistics were used to assess and compare data of these populations. Results: Results indicate that of the 170 individuals who were tested through Agendia’s MammaPrint and BluePrint panels and underwent germline genetic testing, 80 (46.47%) were classified as High-Risk for recurrence on MammaPrint, and 90 (53.53%) were identified as having a Low-Risk for recurrence. Individuals with a high-risk of recurrence had an 18.75% positive germline variant rate compared to the low-risk group with a 12.22% positive rate. 170 individuals with breast cancer were tested and categorized through Agendia’s BluePrint panel. 19 were classified as Basal type, 2 as HER2 type, 90 as Luminal A type, and 50 as Luminal B type. Individuals with Basal type had the highest positive germline rate of 26.32%, compared to HER2 (0%), Luminal A (12.22%), and Luminal B (16.29%).Conclusion: The iGAP real-world evidence database revealed that individuals categorized as having a high risk of breast cancer recurrence through Agendia’s MammaPrint were identified to harbor a pathogenic or likely pathogenic variant 18.75% of the time. An even higher likelihood (26.32%) was seen in individuals with a Basal-Type molecular subtype. This data argues that germline genetic testing should be offered to every individual, regardless of age, identified as having a high risk of breast cancer recurrence and/or a basal-type molecular subtype on Agendia’s tests. Identification of a pathogenic or likely pathogenic variant has clinical management, familial, and potentially reproductive implications. References American Cancer Society, 2021. Citation Format: Brenna G Bentley, Chloe Wernecke, Kelly Bontempo, Maureen Graham, Pat Witworth, Rakesh Patel, Peter Beitsch. Breast cancer patients categorized as high-risk of recurrence and/or basal-type molecular subtype by MammaPrint and BluePrint, respectively, should universally undergo germline genetic testing [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-08-06.

Positive margins following breast-conserving surgery (BCS) are often identified on standard pathology evaluation. Intraoperative assessment of the lumpectomy cavity has the potential to reduce residual disease or reexcision rate following standard of care BCS in real time.To collect safety and initial efficacy data on the novel pegulicianine fluorescence-guided system (pFGS) when used to identify residual cancer in the tumor bed of female patients undergoing BCS.This prospective single-arm open-label study was conducted as a nonrandomized multicenter controlled trial at 16 academic or community breast centers across the US. Female patients 18 years and older with newly diagnosed primary invasive breast cancer or ductal carcinoma in situ DCIS undergoing BCS were included, excluding those with previous breast cancer surgery and a history of dye allergies. Of 283 consecutive eligible patients recruited, 234 received a pegulicianine injection and were included in the safety analysis; of these, 230 were included in the efficacy analysis. Patients were enrolled between February 6, 2018, and April 10, 2020, and monitored for a 30-day follow-up period. Data were analyzed from April 10, 2020, to August 5, 2021.Participants received an injection of a novel imaging agent (pegulicianine) a mean (SD) of 3.2 (0.9) hours prior to surgery at a dose of 1 mg/kg. After completing standard of care (SOC) excision, pFGS was used to scan the lumpectomy cavity to guide the removal of additional shave margins.Adverse events and sensitivity, specificity, and reexcision rate.Of 234 female patients enrolled (median [IQR] age, 62.0 [55.0-69.0] years), 230 completed the trial and 1 patient with a history of allergy to contrast agents had an anaphylactic reaction and recovered without sequelae. Correlation of pFGS with final margin status on a per-margin analysis showed a marked improvement in sensitivity over standard pathology assessment of the main lumpectomy specimen (69.4% vs 38.2%, respectively). On a per-patient level, the false-negative rate of pFGS was 23.7% (9 of 38), and sensitivity was 76.3% (29 of 38). Among 32 patients who underwent excision of pFGS-guided shaves, pFGS averted the need for reexcision in 6 (19%).In this pilot feasibility study, the safety profile of pegulicianine was consistent with other imaging agents used in BCS, and was associated with a reduced need for second surgery in patients who underwent intraoperative additional excision of pFGS-guided shaves. These findings support further development and clinical performance assessment of pFGS in a prospective randomized trial.ClinicalTrials.gov Identifier: NCT03321929.

Background: Racial/ethnic disparities have been well-documented in access to cancer screening and treatment, as well as treatment outcomes. Less is known regarding the yield of genetic pathogenic variants (PVs) in non-white populations. Methods: Patient data was obtained from the Informed Genetics Annotated Patient Registry (iGAP), an IRB-approved multi-center longitudinal, observational study, in which 2148 patients self-declared race/ethnicity and underwent germline genetic testing at any lab. Analyses were limited to 24 cancer susceptibility genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, NBN, PALB2, PTEN, STK11, TP53, APC, BMPR1A, CDK4, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, RAD51C, RAD51D, SMAD4), 21 of which have clinical management guidelines from the NCCN (excluding NBN, BARD1, CDK4).1 Descriptive statistics were used to assess and compare data from these populations and germline genetic testing results. Results: The Registry included 2148 patients, 1662 (77.37%) with a personal history and 1536 (71.51%) with a family history of cancer. The patients were 74.39% White, 6.33% Hispanic, 5.59% African/Black, 5.03% Asian, 1.63% Other, 1.35% Ashkenazi, and 5.68% Unknown. The overall germline PV rate in the cohort was 0.1089 PVs/patient tested, with 234 PVs detected in 227 patients. The PV rate among racial/ethnic groups were as follows: White 170/1598 (0.1064), Asian 8/108 (0.0741), Hispanic 27/136 (0.1985), African/Black 11/120 (0.0917), Ashkenazi 6/29 (0.2069). In patients self-reporting as Hispanic, the PV rate was similar to PV rate in those self-reporting as Ashkenazi, and significantly higher (p=0.00027) than PV rate in those of other self-reported race/ethnicity. Gene level PV rates are shown in Table 1. Conclusions: Those who reported being Hispanic had an increased overall PV rate. This could be due to the greater representation of Hispanics from New Mexico who may have Ashkenazi ethnicity. Further studies are needed to understand whether these differences are a result of disparate access to testing, true population differences, lack of data in non-White populations skewing variant classification or other factors. Table 1. Gene PV Rates by Racial/Ethnic Category. Citation Format: Peter Beitsch, Chloe Wernecke, Rakesh Patel, Barry Rosen, Gia Compagnoni, Ian Grady, Eric Brown, Lindsay Gold, Pat Whitworth, Linda Ann Smith, Mariusz Wirga, Richard Reitherman, Steven Cai, Toan Nguyen, Valerie Traina, Dennis Holmes, Paul Baron, Brittany Krautheim, Anne Peled, Walt Taylor, Kelly Bontempo, Brenna Bentley, Krista Ortega, Pouyan Ahmadi. Racial/Ethnic Groups Have Different Rates of Pathogenic Variants in Common Cancer Genes [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-02-09.

Background: The etiology of melanoma has generally been thought to be exposure to UV radiation (sun and sun tanning lamps). However, the percent of melanoma patients harboring a germline PV is not well studied so we undertook this study to determine the number of patients with melanoma who have a PV. Methods: Patient data was obtained from the Informed Genetically Annotated Patient (iGAP) Registry, an IRB-approved multi-center longitudinal, observational study designed to capture genetic test results and the patient’s outcome over time. A sequential series of unselected melanoma patients presenting to a single surgical oncologist’s office for treatment underwent multigene panel testing. Additionally, patients who had already undergone multigene panel testing for another reason (breast cancer) were included. The cohort was analyzed overall and in two subgroups: melanoma patients who also had a history of breast cancer and melanoma patients who have never had breast cancer. Demographics collected include age at diagnosis, race, other cancers, stage of melanoma, and thickness of melanoma. Results: There were 170 patients, most were Caucasian (one Black, one Asian) and the average age was 60.9 years. There were 11 patients with a history of prior melanoma. There were 39 males and 131 females. Stages ranged from zero to four with a majority of them stage one. Average thickness was 2.1 mm. The overall group (170 patients) had 29 (17.06%) with a PV (one patient with melanoma and breast cancer had three PVs). The following table lists the PVs (see Table 1). There were 56 patients with melanoma and breast cancer, eight (14.3%) of which had a PV. In the melanoma without breast cancer group (n = 114), had 21 (17.5%) had a PV. Conclusions: The cost of germline genetic testing with large panels has fallen precipitously making testing more available for many cancer patients. There have been attempts to define a group of factors in patients with melanoma who should be offered germline testing but with mixed results. Our cohort of melanoma patients (with or without breast cancer) has a PV rate of 17% suggesting that all patients with melanoma should be offered germline genetic testing. Guidelines restricting testing are no longer justified. Table 1. Melanoma PVs Melanoma without Breast Cancer PVs Melanoma with Breast Cancer PVs MUTYH-Monoallelic 3 BLM 2 CHEK2/1100delC 3 ATM 1 NTHL1 2 BRCA1 1 CDKN2A/p16 2 CHEK2 1 SDHA 2 CHEK2/1100delC 1 ATM 2 MITF 1 MITF 2 MUTYH-Biallelic/Compound Heterozygous 1 PMS2 1 NF1 1 MUTYH-Biallelic/Compound Heterozygous 1 PTEN 1 MSH3 1 FH 1 BRCA2 1 Total Melanoma w/o Breast Cancer PVs 21 Total Melanoma w/Breast Cancer PVs 10 Citation Format: Peter Beitsch, Chloe Wernecke, Kelly Bontempo, Brenna Bentley, Pat Whitworth, Rakesh Patel. Germline pathogenic variants in melanoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB163.