Cancer Genomics Community Research Network Research Articles

Germline DNA Repair Genes Pathogenic Variants Among Mexican Patients With Prostate Cancer.

Early identification of germline mutation carriers may be relevant for the optimal management of prostate cancer and to inform cancer risk in relatives. However, population minorities have limited access to genetic testing. The aim of this study was to describe the frequency of DNA repair gene pathogenic variants (PVs) among Mexican men with prostate cancer referred for Genomic Cancer Risk Assessment and testing. Patients diagnosed with prostate cancer who meet criteria for genetic testing and enrolled in the Clinical Cancer Genomics Community Research Network at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán in Mexico City were included. Descriptive statistics were performed using frequency and proportions for categorical variables and median and range for quantitative variables. X2 and t test were used for group comparisons. A total of 199 men were enrolled, median age at diagnosis was 66 (range 44-88) years; 45% were de novo metastatic and 44% were high- very high and 10% were intermediate risk group. Four (2%) had a pathogenic germline variant; one each of the following genes: ATM, CHEK2, BRIP1, and MUTYH (all monoallelic). Younger men at diagnosis were more likely to carry a PV than older age at diagnosis (56.7 vs. 66.4 years, P=.01). Our results showed a low prevalence of known prostate cancer associated PVs and no BRCA PVs in Mexican men with prostate cancer. This suggests that the genetic and/or epidemiologic risk factors for prostate cancer are not well characterized in this specific population.

Spectrum of germline pathogenic variants among patients with cancer in Mexico.

10620 Background: Up to 10% of patients with cancer harbor pathogenic germline variants (PVs) in one or more cancer susceptibility genes. Genetic cancer risk assessment (GCRA) is an important tool for the management of patients with cancer. It allows the identification of candidates for structured screening protocols, risk reduction strategies, targeted therapies and cascade testing. Knowledge about the prevalence and spectrum of PVs is limited among underrepresented populations. We studied the prevalence of germline PVs in a cohort of Mexican patients with cancer. Methods: Between April 2017 and September 2022, patients with diagnosis of cancer who met clinical criteria for GCRA according to international guidelines (NCCN) and were enrolled in the international Clinical Cancer Genomics Community Research Network (CCGCRN) registry at Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran were included. Cancer risk counseling and germline multi-gene panel testing were performed. Post-test counseling and cascade testing with known PV analysis was offered. Results: 1322 patients met inclusion criteria (probands n = 1027, relatives n = 295). Among the probands, 72.4% (744/1027) were women, median age at cancer diagnosis was 48.2 years (range 1-88) and 9.8% (n = 101) had more than one primary tumor. 14.5% (149/1027) of probands had a positive result in which 152 PV were identified ( BRCA1 n = 39, BRCA2 n = 33, ATM n = 11, CHEK2 n = 11, MLH1 n = 11, TP53 n = 7, PALB2 n = 7, NF1 n = 6, MSH2 n = 5, MSH6 n = 3, PTEN n = 3, APC n = 2, BRIP1 n = 2, CDH1 n = 2, RB1 n = 2 and 1 PV in the genes: CDKN2A, MAX, MUTYH, NBN, PTCH1, RAD50, SDHA and SDHB). The frequency of PV according to cancer diagnosis was: breast 15.5% (82/527), prostate 2% (4/198), ovarian 15.6% (12/77), colorectal 26.6% (16/60) and pancreatic 11.9% (5/42). The frequency of recurrent, potentially founder PVs in their respective genes was as follows: BRCA1 del(exons9-12) 30.7% (12/39) and CHEK2 c.707T > C 81.8% (9/11). Among the relatives referred for cascade testing the frequency of PV was 40% (118/295), 18.6% (55/295) had personal history of cancer with a median age at diagnosis of 47 years. Conclusions: Our results show a wide spectrum and a variable frequency of PVs among one of the largest examined cohorts of Mexican patients with cancer, with a high frequency of PVs among cases of breast, ovarian, and colorectal cancer. In contrast to reports from other populations, there was very low frequency of PVs among patients with prostate cancer. The outcomes of this study add to our understanding of the genetic epidemiology of cancer in the Mexican population, and support creating GCRA programs to improve access to multi-gene panel testing among underrepresented patients in limited resource settings.

Abstract P6-02-05: Prevalence of non-BRCA germline pathogenic variants in Mexican women with breast cancer referred for genetic cancer risk assessment

Abstract Background: The prevalence of germline pathogenic variants in Mexican women with breast cancer who met the reference criteria for genetic cancer risk assessment (GCRA) has been previously reported as close to 20%. However, information regarding the spectrum of gPVs in genes other than BRCA in this population is limited. Methods: This prospective study included Mexican women who were diagnosed with BC and met international criteria for GCRA. Participants were enrolled in the Clinical Cancer Genomics Community Research Network (CCGCRN) registry and at two referral breast cancer centers in Mexico, the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City and at the Hospital Zambrano Hellion TecSalud, Monterrey. Participants underwent multigene panel testing (MGPT) for 37 cancer susceptibility genes. For this analysis, only the results of pathogenic and likely pathogenic variants in the index cases were reported. The demographic and molecular characteristics of the variants are described here. Results: From August 2017 to September 2021, 1020 Mexican women with BC underwent MGPT, with a median age at diagnosis of 41 y (range 20-86), of whom 206 (20.2%) were carriers. 208 gPVs were identified with BRCA1/2 representing 70% (145/208) of the gPVs (BRCA1 n=89, BRCA2 n=56). 63 (30%) of gPVs were identified in genes other than BRCA (CHEK2 n=21, PALB2 n=13, TP53 n=7, RAD51C n=5, ATM n=4, NF1 n=3, PTEN n=2, MUTYH homozygous n=2, RAD50 n=1, BRIP1 n=1, CDH1 n=1, NBN n=1, MSH2 n=1 and MSH6 n=1). The recurrent variants previously proposed as founders in the Hispanic population were frequent among those identified in their respective genes: CHEK2 c.707T>C 81% (17/21), PALB2 c.2167_2168delAT 46% (6/13) and BRCA1 del(exons 9-12) 18% (16/89). As a group, the 4 most frequent genes where gPVs were identified (BRCA1, BRCA2, CHEK2 and PALB2) represented 86% (179/208) of the positive results. Conclusion: Among the variants identified in this population of Mexican women with BC, the proportion of gPVs in genes other than BRCA was significant (about 1 out of 3 pts), which justifies the use of MGPT in the assessment of our population. However, a tailored panel (sequencing of BRCA1/BRCA2/CHEK2/PALB2 and MLPA for BRCA1) could be proposed in areas of Mexico with limited medical resources, including the analysis of other genes in selected patients according to clinical suspicion and family history of cancer. Citation Format: Yanin Chavarri-Guerra, Cynthia Villareal Garza, Jose Luis Rodriguez-Olivares, Dione Aguilar-y Mendez, Gregorio Quintero-Beulo, Francisco Gutierrez-Delgado, Josef Herzog, Stephen Gruber. Prevalence of non-BRCA germline pathogenic variants in Mexican women with breast cancer referred for genetic cancer risk assessment [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 P6-02-05.

Abstract 2214: Disparity in the uptake of risk-reducing surgery after GCRA in Hispanic patients in Latin America and in the United States

Abstract Background: Patients at increased risk of breast (BC) and/or ovarian (OC) cancer can opt for risk-reducing surgeries (RRS). However, there are disparities in access to genomic cancer risk assessment (GCRA) and cancer prevention interventions related to geography, socioeconomic status, and limited public health support. We studied factors that affect the uptake of risk-reducing mastectomy (RRM) and salpingo-oophorectomy (RRSO) in Hispanic patients of Latin America (LatAm) and the United States (US). Methods: Hispanic women enrolled in the Clinical Cancer Genomics Community Research Network registry between 1997-2019 who underwent genetic testing, had a personal or family history (FHX) of BC or OC, and had ≥6 months of follow-up data were considered eligible. Demographic and clinical factors associated with risk-appropriate uptake of RRS were considered. Data were analyzed using Fisher’s exact tests and logistic regression models. Results: 1818 patients with a median follow-up of 43 months were studied. Most were from the US (65%), followed by Mexico (21%), Peru (10%), Colombia (2%), and Puerto Rico (2%). Median age at enrollment was 44 years; 81% had a personal history of BC and 5% of OC. Cancer-associated pathogenic variants (PVs) were identified in 459 patients (25%); 409 were in BRCA, 36 had other BC-susceptibility PVs (ATM, CHEK2, PALB2, PTEN, or TP53), and 14 had other OC-susceptibility PVs (BRIP1, MSH2, MSH6, MLH1, or RAD51C). Overall, 449/1715 (26.2%) patients underwent RRM, with a higher rate among patients in the US than those in LatAm (31% vs. 17%, p<0.01); 377/1517 (25%) patients underwent RRSO, with no regional differences observed (24% vs. 27%, p=0.22). The factors associated with undergoing RRM were US residence (OR 2.2; 95% CI 1.7-2.8), age ≤50 (OR 2.2; 95% CI 1.7-2.8), carrying a BC-predisposing PV (OR 3.5; 95% CI 2.8-4.4), positive FHX for BC (OR 1.5; 95% CI 1.2-1.9), and personal history of cancer (OR 3.6; 95% CI 2.4-5.6). In a multivariate model, US residence, age, and previous BC diagnosis remained independent predictors for RRM in BC-susceptibility gene PV carriers, while age was not a significant factor in non-carriers. The factors associated with undergoing RRSO included being a carrier of an OC-predisposing PV (OR 6.3; 95% CI 4.8-8.1), positive FHX for OC (OR 2.1; 95% CI 1.5-2.8), and previous cancer diagnosis (OR 1.7; 95% CI 1.2-2.5). In carriers of OC-susceptibility gene PVs, residing in US and previous cancer diagnosis were independently associated with RRSO, while positive FHX for OC and previous cancer diagnosis were identified as independent factors in non-carriers. Conclusion: There are disparities in the uptake of RRS outside the US. Beyond limitations in resources, understanding the factors associated with undergoing RRS could be key to developing targeted interventions to improve the uptake of risk-appropriate measures in hereditary cancer syndrome patients. Citation Format: Jeffrey N. Weitzel, Yanin Chavarri-Guerra, Ana Ferrigno, Pamela Mora-Alférez, Annette Campbell-Fontaine, Cynthia Villarreal-Garza, Alejandro Mohar-Betancourt, Gubidxa Gutierrez-Seymour, Gary W. Unzeitig, Sandra Brown, Bita Nehoray, Azucena del Toro-Valero, Pamela Ganschow, Ian Komenaka, Yenni Rodriguez, Francisco Gutierrez-Delgado, Kathleen R. Blazer. Disparity in the uptake of risk-reducing surgery after GCRA in Hispanic patients in Latin America and in the United States [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 2214.

Evaluation of Lynch syndrome risk models in a multicenter diverse population.

10597 Background: Lynch syndrome (LS) is the most common cause of hereditary colorectal cancer (CRC) with an increased CRC lifetime risk of 70-80%. LS affects 1:250 individuals and is caused by pathogenic variants in the mismatch repair (MMR) genes. Statistical prediction models such as MMRpro and PREMM5 are widely used to identify LS carriers. However, these models are trained and validated in mostly white populations, and there remains a gap in understanding their performance in Hispanic populations. The purpose of this study was to evaluate the performance of MMRpro and PREMM5 on a large Hispanic cohort from the Clinical Cancer Genomics Community Research Network (CCGCRN). Methods: We validated MMRpro and PREMM5 on 3,490 CCGCRN families, of which 1,122 are Hispanic and 2,062 Non-Hispanic. The two models were evaluated for discrimination using the C-statistic, calibration using the observed to expected ratio (O/E), and overall performance using the root Brier score and negative and positive predictive value (NPV/PPV) at the 5% carrier probability threshold. Evaluations were stratified by ethnicity, and 95% confidence intervals were obtained via bootstrapping for all measures. Results: The C-statistic is 0.90 for both MMRpro (95% CI: 0.88, 0.92) and PREMM5 (95% CI: 0.87, 0.92). When stratified by ethnicity, the C-statistics are 0.96 (95% CI: 0.94, 0.97) and 0.86 (95% CI: 0.83, 0.89) for Hispanics and Non-Hispanics, respectively, in MMRpro, and 0.96 (95% CI: 0.94, 0.97) and 0.84 (95% CI: 0.79, 0.88) in PREMM5. Both models underpredict mutation probabilities, with O/E ratios ranging from 1.79 to 1.96. At a 5% threshold, variations in PPV between Hispanics and Non-Hispanics are observed in both models: 0.72 (95% CI: 0.63, 0.80) and 0.43 (95% CI: 0.37, 0.50) in Hispanic and Non-Hispanic groups in MMRpro; 0.50 (95% CI: 0.43, 0.57) and 0.25 (95% CI: 0.20, 0.30) in PREMM5. We observe less variation and higher values in NPVs in both models. Conclusions: Overall, MMRpro and PREMM5 perform well in this cohort in predicting the probability of having a pathogenic variant in an MMR gene, with modest underprediction. While these results offer reassurance for the clinical use of MMRpro and PREMM5 in Hispanic populations, further validation studies in underrepresented racial and ethnic populations are crucial.

Pathogenic variants among Mexican patients with colorectal cancer referred for genetic cancer risk assessment.

69 Background: Lynch syndrome (LS) is the most frequent hereditary cancer syndrome among patients with colorectal cancer. Screening tests such as immunohistochemistry (IHC) for mismatch repair (MMR) proteins and PREMM5 model help to identify patients at risk of germline pathogenic variants (PVs). However, there has been a disparity in that evaluation of these screening tools and their correlation with pathogenic variants (PVs) has been limited in Hispanic populations. Methods: Patients with colorectal cancer referred for genetic cancer risk assessment were enrolled in the Clinical Cancer Genomics Community Research Network (CCGCRN) registry from October 2017 to February 2021 at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Genetic testing was performed by full sequencing of the MMR genes ( MLH1, PMS2, MSH2, MSH6 and EPCAM) and other cancer-associated genes ( APC, BRCA1, BRCA2, TP53, NF1, ATM, CHEK2, PALB2, BRIP1) and multiplex ligation dependent probe amplification to detect copy number variants (CNV) was performed for selected genes. Demographic, clinical characteristics and IHC results were obtained from clinical records. MMR PV probability was calculated using PREMM5. Results: Sixty-nine patients with colorectal cancer were included; mean age at diagnosis was 50 (26-82) years and 39/69 (56%) were women. A MMR gene PV was identified in 23/69 patients (33%); most frequently in MLH1 n = 14, followed by MSH2 n = 2, MSH6 n = 2 and PMS2 n = 1. Four recurrent PVs in MLH1 and MSH2 represented 22% of PVs. CNVs were identified in 4/23 (17.4%) patients with LS. PVs in other genes were identified in 8.6% of the cases: 2 ATM, 1 APC, 1 PALB2, 1 BRIP1 and 1 BRCA1. IHC results were available in 52/69 cases (75.4%) and MMR protein deficiency was found in 16/17 (94%) carriers and in 14/31 (45%) non-carriers (sensitivity 94.1% and specificity 54.8%). The area under the ROC curve for PREMM5 score was 0.94 (95% CI 0.88-0.99) with a mean score 31.6 (2.4-50) in patients with LS and 4.1 (0.9-50) in non-carriers. The diagnosis of a second primary colon cancer was more frequent among LS (30% vs 2.5%; p < 0.01). Conclusions: We found a high frequency of MMR gene PVs among patients referred for GCRA with personal history of colon cancer, and only a small proportion with PVs in other genes. Our results showed a good performance of PREMM5 model and a high sensitivity of MMR IHQ in a Mexican population, indicating that these are tools that can be used to prioritize patient selection for germline testing.

Germline pathogenic variants among Mexican patients with adenocarcinoma of the pancreas.

540 Background: The reported frequency of germline pathogenic variants (PVs) in patients with pancreatic cancer is 8-10%. Depending on the setting, pancreatic cancer-associated germline PVs in the BRCA and CDKN2A genes are the most commonly detected. The mismatch repair genes (MMR; Lynch syndrome) , TP53, STK11, ATM and PALB2 are also associated with an increased risk of pancreatic cancer . The identification of PVs in patients with pancreatic cancer is important as there may be a benefit of targeted therapies, such as PARP inhibitors for cases with defective double strand break repair or response to immunotherapy with defective MMR and high tumor mutational burden. Additionally, identification of predisposing PVs can enable screening and prevention for other family members through cascade testing. According to international guidelines, all patients diagnosed with exocrine pancreatic cancer are candidates for genetic testing. However, there is an underrepresentation of ethnic/ racial minorities, including Hispanic patients, in genetic studies. Methods: Between April 2017 and May 2020, patients with diagnosis of pancreatic adenocarcinoma who were treated at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán and enrolled in the international Clinical Cancer Genomics Community Research Network registry were included in this analysis. Genetic testing was performed by full sequencing of the following genes: BRCA1, BRCA2, TP53, NF1, ATM, CHEK2, PALB2, CDKN2A, BRIP1, RAD50, RAD51C, RAD51D, MLH1, MSH2, MSH6, PMS2 and EPCAM, as well as multiplex ligation-dependent probe amplification for selected genes and BRCA1 ex9-12del (Mexican founder mutation) screening with a three-primer polymerase chain reaction. Pedigrees, clinical and demographic data were obtained from the clinical records. Results: Forty-two patients with a diagnosis of pancreatic adenocarcinoma were included, with a median age at diagnosis of 57 years (range, 43-79), and 23/42 (55%) were women. The proportion of cases with operable, unresectable and metastatic disease at diagnosis was similar (33.3% for each group). The frequency of PVs was 11.9% ( ATM n =2, TP53 n =1, PALB2 n =1 and CHEK2 n =1). With a median follow-up 20 months 29/42 patients had died at the time of analysis (69%), the median overall survival was 16 months (range 3-84 months). No PVs were detected in the 4/42 patients who met the definition of familial pancreatic cancer (9.5%). Conclusions: Our results confirm the presence of PVs in cancer susceptibility genes in Mexican patients with pancreatic cancer, which is similar to that reported in other populations. However, it is notable that no BRCA PVs were identified in this small sample, as they are the most common PV found in other populations. Given to the heterogeneity of the PVs identified, our study supports the use of multi- gene panel testing in Hispanic patients with pancreatic cancer.

Maintaining access to genomic cancer risk assessment (GCRA) during the COVID-19 pandemic using telemedicine in a resource-limited setting.

286 Background: COVID-19 has disrupted cancer care services globally, and particularly in low- and middle-income countries. The cancer genetics clinic at Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán has provided GCRA for over 1000 underserved Mexican patients with cancer since 2017 through a collaboration with the Clinical Cancer Genomics Community Research Network (CCGCRN). During the COVID-19 pandemic, in-person clinic visits were suspended, and telemedicine emerged as a potential way to provide GCRA while reducing the risk of COVID-19. Here, we report our experience using telemedicine to provide GCRA in a resource-limited setting. Methods: During the COVID-19 pandemic, new patients meeting criteria for GCRA were invited to join the CCGCRN via phone call. Candidates received detailed information regarding the protocol procedures and multigene genetic testing. Those who accepted were sent an electronic consent form, family medical history forms, and risk reduction questionnaires to be completed before their appointment. Blood testing was performed during a short visit to the hospital, or mailed by the patient. Patients who had already received GCRA and genetic testing prior to the start of the pandemic were contacted to cancel their in-person appointment and to schedule a telemedicine visit. According to patient preferences and availability, results were disclosed via phone call, video call, or teleconferencing software employing end-to-end encryption communication apps. Results: Between July 2020 and May 2021, 273 new patients fulfilling GCRA criteria were invited to the CCGCRN protocol. Median age at the time of enrollment was 44 years (range 27-66), 87% (n = 237) were women, and 68% (n = 187) had a personal history of cancer (90% breast). Eighty-three percent of new patients (n = 227) completed all the protocol procedures. Median length of the enrollment phone call was 10 minutes (range 4-71 min). During the same period, 439 genetic testing results (including those of patients who received GCRA before the pandemic and of new patients) were disclosed: 356 were negative and 83 had a pathogenic variant (PV). Ninety-nine percent of patients with negative testing received their results via phone call, and 96% were sent a digital written report. For patients with a PV, 80% of results were disclosed via videoconferencing platforms (WhatsApp or Zoom). All patients with PV were sent a digital written report, risk reduction and early detection recommendations, a family letter, and specific PV information. Conclusions: Providing access to GCRA and testing using readily-available telemedicine platforms proved feasible in a resource-limited setting during the COVID-19 pandemic. Our results show that telemedicine represents an excellent method to identify, recruit, and test patients meeting criteria for GCRA, and to provide genetic testing results.

Genetic epidemiology of BRCA1- and BRCA2-associated cancer across Latin America

The prevalence and contribution of BRCA1/2 (BRCA) pathogenic variants (PVs) to the cancer burden in Latin America are not well understood. This study aims to address this disparity. BRCA analyses were performed on prospectively enrolled Latin American Clinical Cancer Genomics Community Research Network participants via a combination of methods: a Hispanic Mutation Panel (HISPANEL) on MassARRAY; semiconductor sequencing; and copy number variant (CNV) detection. BRCA PV probability was calculated using BRCAPRO. Among 1,627 participants (95.2% with cancer), we detected 236 (14.5%) BRCA PVs; 160 BRCA1 (31% CNVs); 76 BRCA2 PV frequency varied by country: 26% Brazil, 9% Colombia, 13% Peru, and 17% Mexico. Recurrent PVs (seen ≥3 times), some region-specific, represented 42.8% (101/236) of PVs. There was no ClinVar entry for 14% (17/125) of unique PVs, and 57% (111/196) of unique VUS. The area under the ROC curve for BRCAPRO was 0.76. In summary, we implemented a low-cost BRCA testing strategy and documented a significant burden of non-ClinVar reported BRCA PVs among Latin Americans. There are recurrent, population-specific PVs and CNVs, and we note that the BRCAPRO mutation probability model performs adequately. This study helps address the gap in our understanding of BRCA-associated cancer in Latin America.

Abstract PS8-15: The spectrum of germline susceptibility gene variants in Mexican patients with breast cancer (BC): A Prospective Multicenter study

Abstract Background: BRCA mutations are responsible for a significant proportion of hereditary breast and ovarian cancers. However, other cancer susceptibility genes are also associated with an increased risk of developing breast cancer (BC). In Mexico, approximately 15% of patients with BC have been identified with BRCA mutations. Despite our growing understanding of BRCA mutations, the contribution and characterization of non-BRCA mutations in Mexican patients with a BC diagnosis remains unknown. We aimed to investigate the spectrum of BC-associated mutations among Mexican patients with BC referred for genetic cancer risk assessment (GCRA) in the multinational Clinical Cancer Genomics Community Research Network (CCGCRN). Methods: Mexican patients with a primary BC who were enrolled in the IRB-approved CCGCRN registry protocol and underwent genetic counseling and multigene panel testing (MGPT) were included. Pathogenic and likely pathogenic variants (PV) in genes associated with increased BC risk were used for analyses. Clinical and demographic characteristics of BRCA and non-BRCA carriers were compared. Results: From December 2012 to February 2020, 725 Mexican patients with BC who had MGPT results with a median age (years) of 41 (range 25-76) were included. 142 (19.6%) patients carried a BC-associated PV. Of these, 98 (69.0%) carried BRCA PVs: 58 in BRCA1 (41.5%) and 40 in BRCA2 (26.7%). PVs in other BC-associated genes (n = 42) accounted for 29.5% of all observed PVs and were distributed as follows: PALB2 (n = 13), CHEK2 (n = 11), RAD51C (n = 6), ATM (n = 3), PTEN (n = 3), TP53 (n = 3), BRIP1 (n = 2), and CDH1(n = 1). Other actionable genes represented 3.5% of all PVs (PMS2 [n = 3]; MSH6 [n = 1]; MSH2 [n = 1]). Suspected founder mutations in Latinas, PALB2 c.2167_2168delAT (n = 5) and CHEK2 c.707T>C (n = 9), represented 33.3% (n = 14/42) of the detected non-BRCA PVs. Mean age at first cancer diagnosis (years) for BRCA and non-BRCA carriers was: 37 (range 26-58) and 42 (range 25-76) (p<0.05), respectively. Among carriers, those with BRCA PVs had a significantly greater proportion of triple-negative (TN) tumors compared to non-BRCA PVs (45.2% vs 9.5%; p<0.05). Conclusion: A significant proportion of Mexican women carried a BC-associated mutation and a third were non-BRCA PVs. Among non-BRCA PVs, recurrent PALB2 and CHEK2, which had previously been characterized in BRCA-negative US Latinas with BC, were the most common and confirms their presence and clinical impact in Mexico. BRCA carriers were younger and more commonly had the TN molecular subtype. Citation Format: Yanin Chavarri-Guerra, Cynthia Villarreal-Garza, Gubidxa Gutierrez Seymour, Dione Aguilar y Mendez, Jazmin Arteaga-Vazquez, Servando Cardona-Huerta, Adrian Daneri-Navarro, Azucena del Toro Valero, Alejandro Mohar-Betancourt, Andrés Rodríguez-Faure, Jose Luis Rodriguez-Olivares, Gregorio Quintero Beulo, Danielle Castillo, Kai Yang, Joseph Herzog, Rosa Mejia, Sharon Sand, Jeffrey N Weitzel. The spectrum of germline susceptibility gene variants in Mexican patients with breast cancer (BC): A Prospective Multicenter study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-15.

Breast cancer associated pathogenic variants among women 61 years and older with triple negative breast cancer

Women with triple negative breast cancer (TNBC) have a high prevalence of BRCA1 mutations, and current clinical guidelines recommend genetic testing for patients with TNBC aged ≤60 years. However, studies supporting this recommendation have included few older women with TNBC. MethodsGenetic testing results from women aged >60 years with TNBC enrolled in the Clinical Cancer Genomics Community Research Network (CCGCRN) registry were included in this analysis. Prevalence of breast cancer-associated pathogenic variants (PVs) was compared across age groups. ResultsWe identified 151 women with TNBC aged >60 years (median 65 years; SD 5.3). Of these, 130 (86%) underwent genetic testing, and a breast cancer–associated PV was identified in 16 (12.3%; 95% CI 7–19): BRCA1 (n = 6), BRCA2 (n = 5), PALB2 (n = 2), ATM (n = 1) and RAD51C (n = 2). We found no differences in the proportion of patients with close blood relatives with breast (≤50 years) or ovarian cancer (any age) between PV carriers (37.5%) and non-carriers (34.2%) (p = 0.79). Among PV's carriers, the proportion of older women with a BRCA1 PV was lower when compared to younger women (37.5% vs 77.2%; p < 0.01). ConclusionBreast cancer-associated PVs were found in an important proportion of women aged >60 years with TNBC undergoing genetic testing, including greater representation of BRCA2. These results suggest that older women with TNBC should be offered genetic testing, and that their exclusion based on chronologic age alone may not be appropriate.

Clinical conundrums: Developing a strategy for discerning TP53-associated chip and coherent clinical care.

1514 Background: Germline TP53 mutations are associated with Li-Fraumeni syndrome (LFS). However, approximately 20% of commercial laboratory multigene panel test (MGPT)-detected pathogenic TP53 variants represent aberrant clonal expansion (ACE), rather than a germline finding, and are often detected in individuals that lack classic features of LFS. Clonal hematopoiesis (CH) is a form of ACE, and in the absence of an abnormal hemogram is termed Clonal hematopoiesis of indeterminate potential (CHIP). CHIP is often associated with a pathogenic variant (PV) in hematopoietic pathway gene(s) at a variant allele frequency (VAF) less than expected for a heterozygous germline finding. The prevalence increases with age and exposure to chemotherapy. The presence of a skewed VAF is usually noted in a comment on a genetic test result, however, clinicians without genetic training often lack understanding of the comment and need strategies to discern the difference between germline findings, CHIP, and post-zygotic mosaicism. Our studies illuminate possible strategies for discernment for clinicians. Methods: Among 113 cases with MGPT-detected TP53 PVs, enrolled in the Clinical Cancer Genomics Community Research Network registry, we obtained additional tissues, family history and complete blood count (CBC) reports on 42 cases. DNA extracted from formalin fixed paraffin embedded (FFPE) tumor/normal tissues, blood, saliva, eyebrow plucks, was analyzed using a previously validated custom myeloid and CH gene (n = 79) amplicon-based QIAseq panel. PVs with VAF &gt; 2% were included in analyses. Results: Germline status was confirmed for 6 cases (one with a CH PV), post-zygotic mosaicism was supported for 5 cases and 2 were indeterminant. 12 had results supporting ACE/CH, with additional CH-associated PV(s) identified in 5/12 (41%); n = 2 of each TET2, ATM, TP53; and increasing VAF over time for the driver TP53 PV was noted in 2. Of these 2 one was identified to have a hematopoietic malignancy identified through analysis of the CBCs and bone marrow biopsy in parallel with the increasing VAF. Additional results are pending for 7 cases. Conclusions: With the use of our multi-tissue NGS strategy, serial sampling of suspected ACE/CH cases, family history and CBC analyses we were able to discern the status of most TP53 genetic findings. This work has direct translational impact, refining risk estimation and improving the clinical care of patients with TP53 PVs, while avoiding unnecessary LFS-related care and enabling appropriate care for those with ACE.

Communication of genetic testing results and cascade testing among Mexican carriers of cancer-associated variants and their families.

e13541 Background: Most hereditary cancer syndromes exhibit autosomal dominant inheritance. Therefore, communicating results to family members and performing cascade testing is crucial in order to identify individuals at risk and offer them appropriate risk-reducing strategies. The process of communicating medical information within families is highly variable and might be affected by several factors (including culture, education, understanding of results, and family conflicts) which remain understudied among individuals living in developing countries. We sought to investigate communication of results and cascade testing reach within the families of Mexican individuals carrying cancer-associated pathogenic variants (PVs). Methods: Individuals seen at a single center in Mexico City carrying a cancer-associated PV and enrolled in the Clinical Cancer Genomics Community Research Network (CCGCRN) were included. Carriers received genetic counseling at the time of results disclosure, a family letter was provided to facilitate the communication of results, and cascade testing was offered. After &gt;3 months from results disclosure, participants were surveyed regarding genetic testing results communication patterns, performance of cascade testing, and surveillance behaviors. Data was analyzed using descriptive statistics. Results: Among 354 probands, 53 (15%) were identified as carriers of a cancer-associated PV. Mean age was 48.3 (range 21-82) years. Cascade testing (≥1 family member) was initiated in 74% of families (n = 39), with a median of 3 (range 0-16) family members tested per proband. 53 carriers responded the survey (29 probands and 24 relatives). 98% (n = 43) had shared results with their family, and 53% (24/45) had shared them with their treating physicians. Most respondents were receiving active surveillance (n = 36, 80%); with 43% (n = 15) reporting having at least one barrier for complying with surveillance (financial: n = 8; distance to the hospital: n = 3). Around half of the carriers perceived their cancer risk to be of ≥50%. Conclusions: Our results show that both the communication of genetic testing results and the proportion of cascade testing within Mexican families are high. Family involvement in health care decision-making is common in Mexico, as in other Latin American countries, which might lead to improved family communication. However, strategies to improve communication with providers are needed in order to tackle barriers and improve surveillance of individuals carrying cancer associated PVs.

Germline mutation profile among Hispanic women with epithelial ovarian cancer (EOC).

1584 Background: Hospital-based studies have reported a 15% prevalence of BRCA1/ BRCA2( BRCA) mutations, with a slightly higher yield of other predisposition genes on multigene panel testing (MGPT) among women with EOC, and National Comprehensive Cancer Network guidelines recommend genetic cancer risk assessment for women with EOC. However, there is limited data about the genetic epidemiology of EOC among underrepresented populations, such as Hispanics. Consequently, we determined the germline mutation profile of Hispanics with EOC, and compared them with non-Hispanics. Methods: We included all women with a personal history of EOC from the U.S. and Latin America (LatAm; Mexico, Colombia, and Peru), enrolled in the Clinical Cancer Genomics Community Research Network registry. We assessed the prevalence of pathogenic variants (PV) in BRCA1/ BRCA2( BRCA) and other genes, contrasting the germline mutation profile between Hispanics living in LatAm, U.S. Hispanics, women of Ashkenazi Jewish (AJ) ancestry in the US, and other U.S. non-Hispanics. Results: Among 1186 women with EOC (209 from LatAm, 254 U.S. Hispanics l, 78 AJ, and 645 other non-Hispanic), 262 (22%) had a PV in BRCAgenes. Hispanics from LatAm and the U.S. had a similar frequency of BRCAmutations to AJ (30.6%, 29.9%, and 38.4%, respectively; p = 0.14); while non-Hispanics showed a significantly lower frequency of BRCAmutations (14.2%, p = 0.03). The most frequently mutated gene was BRCA1(n = 197, 74.6%), followed by BRCA2(n = 67, 25.3%). Among BRCA-negative cases (n = 924), 59% (n = 545) were evaluated by MGPT and PVs were identified in 2.9% [6 Hispanics (1.2%), 3 AJ (3.8%) and 26 Non-Hispanics (4%)]), of which 66% (n = 23) were in mismatch repair genes ( MSH2, MLH1, MSH6, PMS2), and 34% (n = 12) in other EOC-associated genes ( BRIP1, NBN, PALB2, RAD51C, and RAD51D). Clinically actionable PVs in ATM (n = 4; 0.3% ) and CHEK2 (n = 6; 0.5% ) were also observed. Conclusions: Hispanics with EOC have an elevated frequency of PV, similar to that of classic founder populations such as AJ, and significantly higher than other non-Hispanics. This is partially explained by a high prevalence of recurrent LatAm-specific PV, highlighting the importance of conducting genetic studies in underrepresented populations. There was modest incremental benefit of MGPT.

Germline mutations and onset of lung adenocarcinoma in smokers and nonsmokers.

1518 Background: Eligibility for lung cancer screening is based largely on pack-years of smoking, missing many cases. To propose additional groups for screening, this observational study evaluated whether germline mutations associated with cancer risk accelerate onset of lung adenocarcinoma (LA) in ever- and never-smokers. Methods: Patients with LA and family history of cancer were recruited from our oncology clinic and the Clinical Cancer Genomics Community Research Network. With consent, blood samples were screened by large multi-gene panel for 4 categories of germline mutation [lung cancer-associated genes ( TP53, EGFR); BRCA2; other genes in Fanconi anemia (FA) pathway; other DNA repair genes]. Accelerated failure-time models of age at LA diagnosis, adjusted for sex, ethnicity, and packs per day, were constructed for never-smokers and ever-smokers. Statistical significance, at p&lt;0.05 limited the False Discovery Rate to 5% across 8 hypotheses. Results: In never-smokers with LA (n=104), mutated BRCA2, TP53 or EGFR were associated with younger age at diagnosis, while mutation in other FA or DNA repair gene was not. In ever-smokers with LA (n=65), mutated BRCA2 and other FA gene were associated with younger age at diagnosis, while other mutation categories were not (Table). Conclusions: Regardless of smoking history, BRCA2 mutation carriers experience accelerated onset of LA, as do never-smokers carrying TP53 or EGFR mutation and ever-smokers with mutation in FA gene other than BRCA2. With the exception of TP53 carriers (who merit whole body MRI), lung cancer screening with low-dose computed tomography, starting earlier in adulthood than usual, may be warranted for individuals with germline mutations in these genes. Age at Diagnosis of Lung Adenocarcinoma, by Germline Mutation and Smoking History, Adjusted for Sex, Ethnicity, and Packs per Day. [Table: see text]

Enhancing access to genetic cancer risk assessment (GCRA) in Monterrey, Mexico: The beginning of a prevention program.

e13150 Background: In limited-resource countries like Mexico, GCRA is not routinely provided due to elevated costs, lack of public coverage for testing and prophylactic surgeries, and limited GCRA expertise or awareness among providers and patients. Thus, GCRA services in Mexico are 20 years behind higher income countries, resulting in suboptimal care and limited opportunity for prevention. The Breast Cancer Center TecSalud established formal GCRA services for underserved patients by recruiting a cancer geneticist who provides care at no added expense to patients, building academic collaborations for training and research with City of Hope, and enabling free genetic testing through the Clinical Cancer Genomics Community Research Network, supported in part by the Breast Cancer Research Foundation. Aim: To report the uptake of the GCRA program by patients and relatives at TecSalud from January 2016 - December 2018. Methods: Eligibility includes Mexican women who meet hereditary breast cancer testing criteria and family members of mutation carriers. Risk reduction procedures are covered by Seguro Popular and/or the NGO Fundación Santos y de la Garza Evia. Results: GCRA was offered to 255 patients and 74 at risk relatives, with an increasing reach (proportion of those eligible who access the program). A significant growth of cascade testing and access to risk reduction surgery over time are noted. Conclusions: A growing number of referrals and GCRA visits shows improving reach, possibly due to engagement of the multidisciplinary team and increased patient awareness. The expansion of cascade testing and performance of risk-appropriate surgeries reflects a maturing prevention program. Key determinants of our progress are collaborations that provided us with crucial mentorship, access to genetic assays, as well as the increasing involvement of local leaders, administrators and benefactors for the establishment of vital clinical and research capacity. Multilevel efforts should continue to enhance the delivery of standard of medical care for the most vulnerable and underserved high-risk patients and families. [Table: see text]

The Burden of Breast Cancer Predisposition Variants Across The Age Spectrum Among 10 000 Patients.

Women diagnosed with breast cancer (BC) at an older age are less likely to undergo genetic cancer risk assessment and genetic testing since the guidelines and referrals are biased toward earlier age at diagnosis. Thus, we determined the prevalence and type of pathogenic cancer predisposition variants among women with a history of BC diagnosed at the age of 65 years or older vs younger than 65 years. Prospective registration cohort. The Clinical Cancer Genomics Community Research Network, including 40 community-based clinics in the United States and 5 in Latin America. Women with BC and genetic testing results. Sociodemographic characteristics, clinical variables, and genetic profiles were compared between women aged 65 years and older and those younger than 65 years at BC diagnosis. Among 588 women diagnosed with BC and aged 65 years and older and 9412 diagnosed at younger than 65 years, BC-associated pathogenic variants (PVs) were detected in 5.6% of those aged 65 years and older (n = 33) and 14.2% of those younger than 65 years (n = 1340) (P < .01). PVs in high-risk genes (eg, BRCA1 and BRCA2) represented 81.1% of carriers among women aged 65 years and older (n = 27) and 93.1% of those younger than 65 years (n = 1248) (P = .01). BRCA2 PVs represented 42.4% of high-risk gene findings for those aged 65 years and older, whereas BRCA1 PVs were most common among carriers younger than 65 years (49.7%). PVs (n = 7) in moderate-risk genes represented 21.2% for carriers aged 65 years and older and 7.3% of those younger than 65 years (n = 98; P < .01). CHEK2 PVs were the most common moderate-risk gene finding in both groups. Clinically actionable BC susceptibility PVs, particularly in BRCA2 and CHEK2, were relatively prevalent among older women undergoing genetic testing. The significant burden of PVs for older women with BC provides a critical reminder to recognize the full spectrum of eligibility and provide genetic testing for older women, rather than exclusion based on chronological age alone. J Am Geriatr Soc 67:884-888, 2019.

Abstract P6-09-05: Factors associated with the uptake of risk-reducing surgeries among Hispanic women at high risk of breast and ovarian cancer

Abstract Background: BRCA mutation carriers have an increased lifetime risk of breast and ovarian cancer. Although risk-reducing surgeries have documented utility, social factors, cultural beliefs and access to healthcare may be barriers among the Hispanic population to the uptake of risk-reducing practices. We aimed to describe the uptake of risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) among Hispanic women referred for genetic cancer risk assessment (GCRA) and to identify factors affecting that uptake. Methods: Hispanic women from the US and Latin America (LatAm) (Mexico, Colombia, Peru and Puerto Rico) referred for GCRA and enrolled in the Clinical Cancer Genomics Community Research Network (CCGCRN) registry from 1997 to 2016 were included. Demographic characteristics and data regarding risk-reducing surgeries were obtained from chart reviews and patient reported follow-up questionnaires. Data was analyzed using Fisher's test and x2 statistics with a two-sided p value of &amp;lt;0.05 considered significant. An adjusted logistic regression model including a set of significant factors was constructed in order to predict the likelihood of undergoing risk-reducing surgery. Results: Information about risk-reducing surgery status was collected on 1,784 Hispanic women referred for GCRA. Median age was 44.6 years (range 19-98), 84% (n=1506) had a personal history of any type of cancer and 18% (n=323) were BRCA carriers. Median follow-up was 2.6 years. 389 (22%) women had RRM, 167 (17%) had RRSO and 64 (4%) had both surgeries. RRM and RRSO occurred 32 days (SD 983.8) and 228 days (SD 1050.9) after GCRA, respectively. Among BRCA carriers, the rates of RRM and RRSO were 39.42% (n = 123) and 42.66% (n = 93), respectively. The frequency of RRM and RRSO among Hispanic BRCA carriers living in the US was higher than among those living in LatAm (53 vs. 29%, p &amp;lt; 0.01) and (67 vs 21.5%, p &amp;lt; 0.01), respectively. On multivariate analysis, the following factors were associated with a higher likelihood of undergoing RRM: BRCA positive status (HR 5.4, p&amp;lt; 0.01), personal history of breast cancer (HR 6.05, p &amp;lt; 0.01), living in the US (HR 6.53, p&amp;lt; 0.01) and one or more previous pregnancies (HR 1.42, p&amp;lt; 0.01). Educational level, marital status and age were not associated with a likelihood of undergoing RRM. BRCA positive status (HR 12.41, p&amp;lt; 0.01), living in the US (HR 4.23, p&amp;lt;0.01) and age &amp;gt;45 years (HR 2.41, p&amp;lt;0.01) were associated with a higher likelihood of RRSO. Educational level, marital status and family history of cancer were not associated with a higher likelihood of undergoing RRSO. Conclusions: Our results suggest that the rate of RRM and RRSO among Hispanic women is lower than those reported in previous studies in other populations. Hispanic women living in US, BRCA carriers, and women with a personal history of cancer were more likely to have risk-reducing surgeries, which may be a reflection of disparities in access to care between countries and fragmented health systems, as well as of knowledge and cultural barriers. New strategies are warranted in order to improve the uptake of risk-reducing strategies among Hispanic women at an increased risk of cancer. Citation Format: Chavarri-Guerra Y, Yang K, Komenaka I, Brown S, Del Toro Valero A, Mora Alférez P, Duncan P, Rodríguez Y, Ganschow P, Campbell-Fontaine A, Unzeitig G, Horcasitas D, Feldman NR, Slavin T, Nehoray B, Guerrero-Llamas N, Mejia R, Sand S, Blazer K, Weitzel J. Factors associated with the uptake of risk-reducing surgeries among Hispanic women at high risk of breast and ovarian cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-09-05.

Genetic Gastric Cancer Susceptibility in the International Clinical Cancer Genomics Community Research Network

Few susceptibility genes for gastric cancer have been identified. We sought to identify germline susceptibility genes from participants with gastric cancer from an international hereditary cancer research network. Adults with gastric cancer of any histology, and with a germline DNA sample (n = 51), were retrospectively selected. For those without previously identified germline mutations (n = 43), sequencing was performed for 706 candidate genes. Twenty pathogenic or likely pathogenic variants were identified among 18 participants. Eight of the 18 participants had previous positive clinical testing, including six with CDH1 pathogenic or likely pathogenic variants, and two with pathogenic MSH2 and TP53 variants. Of the remaining 10, six were in BRCA1 DNA damage response pathway genes (ATM, ATR, BRCA2, BRIP1, FANCC, TP53), other variants were identified in CTNNA1, FLCN, SBDS, and GNAS. Participants identified with pathogenic or likely pathogenic variants were younger at gastric cancer diagnosis than those without, 39.1 versus 48.0 years, and over 50% had a close family member with gastric cancer (p-values < 0.0001). In conclusion, many participants were identified with mutations in clinically-actionable genes. Age of onset and family history of gastric cancer were mutation status predictors. Our findings support multigene panels in identifying gastric cancer predisposition.

Abstract 4273: Variant reclassifications in hereditary cancer genetics and their implications for clinical care

Abstract BACKGROUND: Clinicians who provide genetic cancer risk assessment (GCRA) are dependent on laboratory reporting of germline results to inform cancer screening and treatment recommendations. Efforts to enhance variant classification and harmonization, such as ClinVar, will lead to an increase in the number of variants being reclassified. Given that the impact of variant reclassification on care is unknown, we evaluated the frequency and clinical impact of variant reclassification on individuals seen for GCRA. METHODS: We retrospectively evaluated data on 7,356 participants enrolled through the Clinical Cancer Genomics Community Research Network (CCGCRN) at City of Hope and Olive View Medical Center from September 1996- October 2016. RESULTS: 4,969 commercial genetic tests yielded a total of 1,610 variants of any category, of which 181 unique variants in 20 genes were reclassified. BRCA1 and BRCA2 (BRCA) and mismatch repair genes comprised 73.5% and 5.5% of the genes reclassified, respectively. Reclassification impacted 225 individuals (97% women) from 217 families; 89% of these individuals (n=201) had a personal history of cancer. The interval between initial report and variant reclassification averaged 3 years (17 days- 13 years). Minorities had higher reclassification rates as compared to non-Hispanic white participants (P = 0.0149). Of the 181 unique reclassifications, 164 (90.6%) of variants were downgraded. Sixteen reclassifications led to changes in clinical care. Thirteen variants carried by 15 individuals were upgraded from a variant of uncertain significance (VUS) to likely pathogenic or pathogenic (10 BRCA, 3 MLH1 or MSH2). These reclassifications prompted additional prophylactic surgical interventions (i.e., bilateral salpingo-oophorectomy), specialist referrals, and surveillance recommendations for at risk patients and family members. Three variants (NBN p.Arg215Trp, PTEN p.Ala79Thr, and MET c.1200+2T&amp;gt;C) were downgraded from likely pathogenic or pathogenic to VUS. Prior to downgrade to VUS, 2 cases had unnecessary surveillance procedures. CONCLUSIONS: Since many genomic variants will be reclassified over time, it is critical that laboratories deliver prompt notification of reclassifications, and that providers involved in GCRA discuss the possibility of variant reclassification with patients and family members and collect patient/proxy information during informed consent so that re-contact is possible. Given the non-trivial effort required for variant reclassification and patient/participant re-contact, system-level interventions are needed to facilitate genomic reinterpretation and the return of results to individuals over time. Citation Format: Thomas P. Slavin, Stacy W. Gray, Lily R. Van Tongeren, Ilana Solomon, Christina Rybak, Bita Nehoray, Lili Kuzmich, Mariana Niell-Swiller, Kathleen R. Blazer, Kai Yang, Julie Culver, Sharon Sand, Danielle Castillo, Josef Herzog, Jeffrey N. Weitzel. Variant reclassifications in hereditary cancer genetics and their implications for clinical care [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4273. doi:10.1158/1538-7445.AM2017-4273